Universal ABT compounds and uses thereof

Abstract

The present disclosure provides, inter alia, compounds comprising a universal antibody binding moiety and a targeting moiety. In some embodiments, the provided compounds recruit various types of antibodies to diseased cells (e.g., cancer cells) and induce immune activity to kill such cells. The provided techniques are useful for the treatment of a variety of diseases, including cancer.

Description

This application is a divisional application of the invention patent application with application date of July 26, 2018, application number 2018800620458, and invention name “Universal ABT compounds and their uses”. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62 / 537,034, filed on July 26, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to compounds and methods that can be used to recruit antibodies to cancer cells. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods of using the compositions for treating various diseases. Background Art

[0003] Immune system activity can be used to prevent or treat a variety of conditions, disorders, and diseases. Summary of the Invention

[0004] In some embodiments, the present disclosure provides technologies, such as compounds, compositions, methods, etc., that are particularly useful for recruiting antibodies to damaged or defective tissues (e.g., tumors, certain wounds, etc.), foreign objects or entities (e.g., infectious agents), etc. In some embodiments, the provided technologies can trigger, generate, promote and / or enhance immune system activities against target cells, tissues, objects and / or entities, such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), etc. In some embodiments, the present disclosure relates to the design and synthesis of new small molecules that are capable of selectively redirecting endogenous antibodies to diseased cells (e.g., cancer cells) and inducing immune system activities, such as antibody-directed cell-mediated immune responses, such as cytotoxicity, ADCP, etc.

[0005] Although still in its infancy, the concept of using small molecules to template the human immune response has shown realistic potential. Recent reports have shown that small molecules have been used to direct antibodies to cancer cells, such as breast cancer cells, melanoma cells and nasopharyngeal epidermal cancer cells. Animal studies have shown that these molecules can promote tumor rejection and anti-tumor immunity in mice. In some embodiments, such molecules can promote tumor regression and / or inhibit tumor growth. Because this process allows endogenous antibodies to be selectively directed to target cells, it has the potential to utilize the power of many immunotherapies (for example, therapeutic agents based on monoclonal antibodies (monoclonal antibody, mAb)), while limiting the cost and side effects associated with the administration of exogenous antibodies. By developing a similar method in which antibodies are recruited to diseased cells (for example, cancer cells), the proposed research will help to broaden this field and potentially produce new treatments for a variety of diseases.

[0006] In some embodiments, the disclosure provides antibody recruitment molecules, which include antibody binding moieties and target binding moieties optionally through a linker moiety. In some embodiments, antibody recruitment molecules (antibody recruiting molecule, ARM) are a class of compounds consisting of two functional segments (functionalsegment) (target binding terminus (TBT) and antibody binding terminus (ABT)) connected by a linker. The target binding moiety (e.g., target binding terminus) can be given ARM specificity to its target (e.g., target diseased cells) by, for example, binding to a receptor that distinguishes (differentiating) targets from non-targets (e.g., diseased cells from other cell types). ARM can especially enable target-specific recruitment of antibodies (e.g., endogenous antibodies, administered antibodies, etc.) by ABT, and / or trigger, produce, promote and / or enhance immune activity (e.g., immune-mediated target cell killing). Without being bound by any particular theory, previous work from the Spiegel laboratory has reportedly shown that ARM-directed killing is primarily mediated by natural killer (NK) cells and macrophages, with the primary receptor involved in this process being CD16a (or FCγRIIIa).

[0007] Previously reported ABTs (e.g., those explored in the Spiegel lab) have focused on molecules (antigens) that bind to the variable region of antibody Fabs. The present disclosure, in particular, encompasses the recognition that the therapeutic success of this approach depends on the presence of sufficient levels of a specific antibody population, which can vary greatly between individuals. In some embodiments, the present disclosure provides techniques that can circumvent the dependency on a specific antibody population and the undesirable effects that can be caused by individual variations in that population. In particular, in some embodiments, the present disclosure provides ARMs comprising ABTs that can bind to the Fc region of an antibody and, thus, can particularly recruit antibodies with various antigen specificities ("universal ABTs" or "uABTs"). In some embodiments, the applicant describes a class of ABTs that utilize conserved sites present in the Fc region of IgG. In some embodiments, uABTs enable the recruitment of all IgG subclasses (IgG1, IgG2, IgG3, IgG4). In some embodiments, uABTs enable preferential recruitment of IgG1, IgG2, and / or IgG4. In some embodiments, recruitment of antibodies (eg, IgG subclass) is limited only by the administered dose of ARM, and / or is not limited by the level of antibodies with a particular Fab region in an individual.

[0008] To provide ARMs containing uABTs, the applicants evaluated the suitability of a number of peptides that have been reported to bind to human IgG Fc for use in the ARM platform. In some embodiments, an essential component of evaluating the therapeutic utility of this strategy is to show that antibodies recruited in this direction are able to bind to and activate CD16a.

[0009] Biochemical and cell-based assays have shown that a series of Fc-binding cyclic peptides can indeed bind to antibodies in a manner that facilitates CD16a activation and are suitable for use on the ARM platform. In some embodiments, the present disclosure shows that uABT can bind to a variety of antibodies. In some embodiments, in addition to having affinity for all human IgG subclasses, these peptides are highly species cross-reactive (binding to secondary antibodies from goats, rabbits, and mice) in exploring different evaluation methods. In some embodiments, uABT binds to IgG molecules but not to human IgA or IgM.

[0010] A variety of TBTs can be used according to the present disclosure. In the attempt to find effective cell targets for cancer treatment, researchers have attempted to identify transmembrane or other tumor-associated polypeptides that are specifically expressed on the surface of one or more specific types of cancer cells compared to one or more normal non-cancerous cells. Generally speaking, such tumor-associated polypeptides are expressed in larger amounts on the surface of cancer cells compared to the surface of non-cancerous cells. The identification of such tumor-associated cell surface antigen polypeptides (i.e., tumor-associated antigens (TAA)) has produced the ability to specifically target cancer cells for destruction. TBTs that selectively bind to TAAs can target target cancer cells and enable cell-specific recruitment of antibodies (e.g., endogenous antibodies) by ABTs. Other suitable TBTs are provided in the present disclosure.

[0011] In some embodiments, the present disclosure provides compounds and pharmaceutically acceptable compositions thereof that effectively recruit antibodies to diseased cells (e.g., cancer cells). In some embodiments, the compound provided induces antibody-dependent effector function. In some embodiments, the compound provided induces complement-dependent cytotoxicity (CDC). In some embodiments, the compound provided induces direct cytotoxicity. In some embodiments, the compound provided inhibits biological functions associated with spatial blocking. In some embodiments, the compound provided induces antibody-dependent cell-mediated virus inhibition (ADCVI). In some embodiments, the compound provided induces ADCC and kills cancer cells. In some embodiments, the compound provided induces ADCP and kills cancer cells. In some embodiments, the compound provided induces both ADCC and ADCP.

[0012] In some embodiments, the present disclosure provides a pharmaceutical agent comprising: Antibody binding portion, a target binding moiety, and an optional linker moiety, The antibody binding portion can bind to two or more antibodies having different Fab regions.

[0013] In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) binds to the Fc region of an antibody. In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) binds to the conserved Fc region of an antibody. In some embodiments, the antibody binding portion binds to the Fc region of an IgG antibody.

[0014] In some embodiments, the present disclosure provides compounds having the general formula I or pharmaceutically acceptable salts thereof: wherein each variable is as defined and described herein. In some embodiments, the provided agent is a compound of Formula I or a salt thereof.

[0015] In some embodiments, the pharmaceutical agent provided is a compound of Formula Ia or a salt thereof. In some embodiments, the present disclosure provides a compound of Formula Ia or a pharmaceutically acceptable salt thereof: wherein each variable is as defined and described in this disclosure. In some embodiments, provided compounds of Formula I are compounds of Formula Ia.

[0016] In some embodiments, the pharmaceutical agent provided is a compound of Formula Ib or a salt thereof. In some embodiments, the present disclosure provides a compound of Formula Ib or a pharmaceutically acceptable salt thereof: wherein each variable is as defined and described in this disclosure. In some embodiments, provided compounds of Formula I are compounds of Formula Ib.

[0017] In some embodiments, the agents and compounds of the present disclosure and their pharmaceutically acceptable compositions are effective in recruiting antibodies to diseased cells, such as cancer cells. In some embodiments, the present disclosure provides a compound having the general formula II or a pharmaceutically acceptable salt thereof: wherein each variable is as defined and described herein. In some embodiments, the provided agent is a compound of formula II or a salt thereof. In some embodiments, the provided compound of formula I is a provided compound of formula II or a salt thereof. In some embodiments, the compound having the structure of formula Ia is a compound of formula II.

[0018] In some embodiments, the present disclosure provides a compound having the general formula III or a pharmaceutically acceptable salt thereof: wherein each variable is as defined and described herein. In some embodiments, the provided agent is a compound of formula III or a salt thereof. In some embodiments, the provided compound of formula I is a provided compound of formula III or a salt thereof. In some embodiments, the compound having the structure of formula Ib is a compound of formula III.

[0019] The compounds of the present disclosure and pharmaceutically acceptable compositions thereof can be used to treat a variety of diseases, disorders or conditions. Such diseases, disorders or conditions include those described herein. In some embodiments, the condition, disorder or disease is cancer. DETAILED DESCRIPTION 1. General Description of Certain Embodiments of the Invention:

[0020] In some embodiments, the present disclosure provides an ARM agent comprising an antibody binding portion ("uABT") that can bind to antibodies with different Fab structures. In particular, in some embodiments, the present disclosure provides an agent comprising an antibody binding portion that binds to the Fc region of an antibody, and such binding to the Fc region of an antibody does not interfere with one or more immune activities of the antibody, such as interaction with an Fc receptor (e.g., CD16a), recruitment of effector cells such as NK cells for ADCC, macrophages for ADCP, etc. As will be appreciated by those skilled in the art, the technology (agents, compounds, compositions, methods, etc.) provided herein comprising uABTs can provide multiple advantages, such as the technology provided can utilize antibodies with multiple Fab regions in the immune system to avoid or minimize the undesirable effects of antibody variation between patient populations, and can trigger and / or enhance immune activity against a target, for example, killing target diseased cells, such as cancer cells.

[0021] In some embodiments, the technology of the present disclosure can be used to recruit antibodies to cancer cells. In some embodiments, the technology provided can be used to regulate the immune activity for targets (diseased cells, foreign objects or entities, etc.), such as ADCC, ADCP, and combinations thereof. In some embodiments, the technology provided can be used to regulate ADCC for target cells (e.g., diseased cells, such as cancer cells). In some embodiments, the technology provided can be used to regulate ADCP for target cells (e.g., diseased cells, such as cancer cells). In some embodiments, the agent provided can inhibit protein activity. In some embodiments, the target binding portion is an inhibitor portion. In some embodiments, the target binding portion is an enzyme inhibitor portion.

[0022] In some embodiments, the present disclosure provides a pharmaceutical agent comprising: Antibody binding portion, a target binding moiety, and an optional linker moiety, The antibody binding portion can bind to two or more antibodies having different Fab regions.

[0023] In some embodiments, provided agents comprise two or more antibody binding moieties. In some embodiments, provided agents comprise two or more target binding moieties.

[0024] The antibody binding portion can interact with any part of the antibody. In some embodiments, the antibody binding portion is combined with the Fc region of the antibody. In some embodiments, the antibody binding portion is combined with the conserved Fc region of the antibody. In some embodiments, the antibody binding portion is combined with the Fc region of the IgG antibody. As will be appreciated by those skilled in the art, a variety of antibody binding portions, linkers and target binding portions can be utilized according to the present disclosure. As shown in the examples, in some embodiments, the present disclosure especially provides antibody binding portions, linkers and target binding portions, and combinations thereof, which are particularly useful and effective for constructing ARM molecules to recruit antibodies to target cells and / or trigger, produce, promote and / or enhance immune system activity against target cells (e.g., diseased cells, such as cancer cells).

[0025] In some embodiments, the present disclosure provides antibody binding portions and / or agents comprising antibody binding portions (e.g., compounds of various formulae described in the present disclosure, ARM molecules of the present disclosure, etc.) that can bind to an Fc region that has bound to an Fc receptor, such as FcγRIIIa, CD16a, etc. In some embodiments, moieties and / or agents comprising antibody binding portions that bind to a complex comprising an Fc region and an Fc receptor are provided. In some embodiments, the present disclosure provides a complex comprising: A medicament comprising: Antibody binding portion, a target binding moiety, and an optional linker moiety; Fc region; and Fc receptors, The antibody binding portion of the agent can bind to two or more antibodies having different Fab regions.

[0026] In some embodiments, the Fc region is an Fc region of an endogenous antibody in the subject. In some embodiments, the Fc region is an Fc region of an exogenous antibody. In some embodiments, the Fc region is an Fc region of an administered agent. In some embodiments, the Fc receptor is a diseased cell in the subject. In some embodiments, the Fc receptor is a cancer cell in the subject.

[0027] In certain embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof: in: ABT is the antibody binding portion; L is a divalent linker moiety connecting ABT to TBT; and TBT is the target binding moiety.

[0028] In some embodiments, the ABT is a universal antibody binding moiety.

[0029] In some embodiments, the antibody binding portion comprises one or more amino acid residues. In some embodiments, the antibody binding portion is a peptide portion or comprises a peptide portion. In some embodiments, the antibody binding portion is a cyclic peptide portion or comprises a cyclic peptide portion. In some embodiments, such an antibody binding portion comprises one or more natural amino acid residues. In some embodiments, such an antibody binding portion comprises one or more non-natural natural amino acid residues. In some embodiments, the amino acid has the structure of Formula AI or a salt thereof: NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -COOH AI, in: R a1 、R a2 、R a3 Each independently is -L a -R'; L a1 and L a2 Each is independently L a ; Each L a are independently covalent bonds, or optionally substituted selected from C1-C 20 aliphatic or C1-C ... 20 a heteroaliphatic divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently an optionally substituted divalent group selected from the group consisting of: C 3-20 Cycloaliphatic ring, C 6-20 aryl rings, 5- to 20-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or an optionally substituted group selected from the group consisting of: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form together a covalent bond, or: two or more R groups on the same atom optionally and independently taken together with that atom form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to that atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0030] In some embodiments, the antibody binding portion is a cyclic peptide portion. In some embodiments, the disclosure provides a compound of Formula Ia or a salt thereof: in: Each Xaa is independently an amino acid residue; t is 0 to 50; z is 1 to 50; L is the connector part; TBT is the target binding moiety; Each R c Independently -L a -R'; a and b are each independently 1 to 200; Each L a are independently covalent bonds, or optionally substituted selected from C1-C 20 aliphatic or C1-C ... 20 a heteroaliphatic divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently an optionally substituted divalent group selected from the group consisting of: C 3-20 Cycloaliphatic ring, C 6-20 aryl rings, 5- to 20-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or an optionally substituted group selected from the group consisting of: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form together a covalent bond, or: two or more R groups on the same atom optionally and independently taken together with that atom form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to that atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0031] In some embodiments, a is 1. In some embodiments, b is 1. In some embodiments, a is 1 and b is 1, and the compound of Formula Ia has structure.

[0032] In some embodiments, each amino acid residue (e.g., each Xaa in Formula Ia) is independently the residue of an amino acid having the structure of Formula AI. In some embodiments, each Xaa independently has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 In some embodiments, two or more side chains of an amino acid residue (e.g., in a compound of Formula Ia) (e.g., R a2 or R a3 R with another amino acid residue a2 or R a3 ) are optionally joined together to form a bridge (e.g., compounds I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.), for example, in some embodiments, the two cysteine ​​residues form an -SS- bridge, as commonly observed in natural proteins. In some embodiments, the bridge formed has L b The structure of L b is L as described in this disclosure a In some embodiments, L b Each end of is independently connected to the backbone atom of the cyclic peptide (e.g., in Formula Ia, -(Xaa) z -ring atoms of the ring formed). In some embodiments, L b Contains an R group (for example, when L b When the methylene unit is replaced by -C(R)2- or -N(R)-), wherein the R group is the same as the R group attached to the backbone atom (e.g., R a1 、R a2 、R a3 In some embodiments, L b The link to the ring is through the side chain of an amino acid residue (e.g., Xaa in Formula Ia), e.g., -(Xaa) in Formula Ia z In some embodiments, such side chains comprise amino or carboxylic acid groups.

[0033] In some embodiments, is the antibody binding portion ( In some embodiments, is a universal antibody binding portion. In some embodiments, It is a universal antibody binding portion that can bind to antibodies with different Fab regions. In some embodiments, is a universal antibody binding portion that can bind to the Fc region. In some embodiments, An antibody binding portion of a structure (e.g., a universal antibody binding portion) can bind to an Fc region that binds to an Fc receptor. In some embodiments, an antibody binding portion, e.g., having The antibody binding portion of the structure has In some embodiments, have structure.

[0034] In certain embodiments, the present invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof: in: R 1 、R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R 1 and R 1’ optionally together with its intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3’ optionally together with its intervening carbon atoms form a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R attached to the same carbon atom 5 Group and R 5’ The group optionally forms, together with its intervening carbon atom, a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or Two R's 5The group optionally forms a C 1-10 An optionally substituted divalent linear or branched, saturated or unsaturated hydrocarbon chain in which 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -C 1 -replace, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1’ 、R 3’ and R 5’ are each independently hydrogen or optionally substituted C 1-3 aliphatic; R 2 、R 4 and R 6 are each independently hydrogen or optionally substituted C 1-4 Aliphatic, or: R 2 and R 1 optionally taken together with its intervening atoms to form a 4- to 8-membered, optionally substituted, saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 optionally taken together with its intervening atoms to form a 4- to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 6 Group and its adjacent R 5 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; L 1 It will a connected trivalent linker moiety; L 2 Is a covalent bond or C 1-30 An optionally substituted divalent linear or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 10 methylene units of the chain are independently and optionally replaced by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 -replace, where each -Cy1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; TBT is a target binding moiety; and m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0035] In some embodiments, the antibody binding portion is or comprises a peptide portion. In some embodiments, the disclosure provides a compound having the structure of Formula Ib or a salt thereof: in: Each Xaa is independently an amino acid residue; each z is independently 1 to 50; Each L is independently a linker moiety; TBT is the target binding moiety, Each R c Independently -L a -R'; a1 and a2 are each independently 0 or 1, wherein at least one of a1 and a2 is not 0; a and b are each independently 1 to 200; Each L a are independently covalent bonds, or optionally substituted selected from C1-C 20 aliphatic or C1-C ... 20 a heteroaliphatic divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently an optionally substituted divalent group selected from the group consisting of: C 3-20 Cycloaliphatic ring, C 6-20 aryl rings, 5- to 20-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or an optionally substituted group selected from the group consisting of: C 1-30aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form together a covalent bond, or: two or more R groups on the same atom optionally and independently taken together with that atom form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to that atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0036] In some embodiments, a1 is 1. In some embodiments, a2 is 1. In some embodiments, b is 1. In some embodiments, the compound of Formula Ib has In some embodiments, the compound of formula Ib has In some embodiments, the compound of formula Ib has In some embodiments, the compound of formula Ib has structure.

[0037] In some embodiments, each amino acid residue (e.g., each Xaa in Formula Ib) is independently the residue of an amino acid having the structure of Formula AI. In some embodiments, each Xaa independently has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 In some embodiments, two or more side chains of an amino acid residue (e.g., in a compound of Formula Ia) (e.g., R a2 or R a3 R with another amino acid residue a2 or R a3) are optionally joined together to form a bridge (e.g., compounds I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.), for example, in some embodiments, the two cysteine ​​residues form an -SS- bridge, as commonly observed in natural proteins. In some embodiments, the bridge formed has L b The structure of L b is L as described in this disclosure a In some embodiments, L b Each end of is independently connected to the backbone atom of the cyclic peptide (e.g., in Formula Ia, -(Xaa) z -ring atoms of the ring formed). In some embodiments, L b Contains an R group (for example, when L b When the methylene unit is replaced by -C(R)2- or -N(R)-), wherein the R group is the same as the R group attached to the backbone atom (e.g., R a1 、R a2 、R a3 In some embodiments, L b The link to the ring is through the side chain of an amino acid residue (e.g., Xaa in Formula Ia), such as -(Xaa) in Formula Ib. z In some embodiments, such side chains comprise amino or carboxylic acid groups.

[0038] In some embodiments, R c -(Xaa)z- is the antibody binding portion (R c -(Xaa)zH binds to the antibody). In some embodiments, R c -(Xaa)z- is a universal antibody binding portion. In some embodiments, R c -(Xaa)z- is a universal antibody binding moiety that can bind to antibodies with different Fab regions. c -(Xaa)z- is a general antibody binding portion that can bind to the Fc region. In some embodiments, the c -(Xaa)z- structured antibody binding portion (e.g., universal antibody binding portion) can bind to an Fc region that binds to an Fc receptor. c -(Xaa)z- has In some embodiments, R c -(Xaa)zL- has structure.

[0039] In certain embodiments, the present invention provides a compound of formula III or a pharmaceutically acceptable salt thereof: in: Each R 7 is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R attached to the same carbon atom 7 Group and R 7 The group optionally forms, together with its intervening carbon atom, a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3- to 8-membered optionally substituted saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; Each R 7 ' is independently hydrogen or optionally substituted C 1-3 aliphatic; Each R 8 are independently hydrogen or optionally substituted C 1-4 Aliphatic, or: R 8 Group and its adjacent R 7 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 9 is hydrogen, optionally substituted C 1-3 aliphatic, or -C(O)-(optionally substituted C 1-3 aliphatic); L 3 It will a divalent linker moiety connected to TBT; TBT is a target binding moiety; and o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 2. Compounds and Definitions:

[0040] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For purposes of the present invention, the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Ed) to identify chemical elements. In addition, the general principles of organic chemistry are described in the following: "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0041] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle," "cycloaliphatic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not aromatic, which has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, which has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0042] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system with at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is a non-branched atomic chain or atom or valence bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom bonded to three or more backbone atoms (excluding hydrogen) of a ring system. In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include those groups shown below, wherein each group is connected to the rest of the molecule on any substitutable carbon or nitrogen atom. Unless otherwise indicated, a bridged bicyclic group is optionally substituted by one or more substituents described for an aliphatic group. In addition or as an alternative, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include:

[0043] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0044] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0045] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0046] As used herein, the term "unsaturated" refers to a moiety having one or more units of unsaturation.

[0047] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched hydrocarbon chain” refers to straight or branched divalent alkylene, alkenylene and alkynylene chains as defined herein.

[0048] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0049] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0050] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl radical having the following structure:

[0051] The term "halogen" refers to F, Cl, Br or I.

[0052] The term "aryl" when used alone or as part of a larger moiety as in "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl or tetrahydronaphthyl, etc. are also included within the scope of the term "aryl".

[0053] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 pi electrons shared in the ring array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, iso Azolyl, As used herein, the terms "heteroaryl" and "heteroaromatic-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, wherein the linking group or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phen ... Phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4- Oxazin-3(4H)-one. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which encompasses optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0054] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably 1 to 4, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used to refer to a ring atom of a heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0055] The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, Oxazolidinyl, piperazinyl, di Alkyl (dioxanyl), dioxolanyl (dioxolanyl), diazepine diazepinyl, oxazepinyl, thiazolinyl The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclyl group" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0056] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0057] As described herein, the compounds of the present invention may include "optionally substituted" parts. Generally speaking, the term "substituted", whether or not preceded by the term "optionally" refers to that one or more hydrogens of the specified part are replaced by suitable substituents. Unless otherwise indicated, the "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combination of substituents contemplated by the present invention is preferably that which results in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and in certain embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0058] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be Ro Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substitution; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be replaced by R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-N(R o )C(NR o )N(R o )2;-(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ;-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-、-SC(S)SR o ; -(CH2) 0-4 SC(O)R o ; -(CH2)0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ; -(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;-SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above limitations, two independent occurrences of R oTogether with its intervening atoms, it forms a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0059] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed by the ring and its intervening atoms are independently halogen, -(CH2) 0-2 R · 、-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2、-O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0- 2SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · , or -SSR · , where each R · is unsubstituted or, in the case of being preceded by "halo", substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0060] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R* 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, where each independent occurrence of R * Selected from hydrogen, C 1-6 an aliphatic (which may be substituted as defined below), or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bound to an ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * Selected from hydrogen, C 1-6 An aliphatic (which may be substituted as defined below), or unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0061] In R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2, or -NO2, where each R · is unsubstituted or, in the case of being preceded by "halo", substituted only with one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0062] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1-6aliphatic (which may be substituted as defined below), unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above limitations, two independent occurrences of Together with its intervening atoms, it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0063] exist Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, in the case of being preceded by "halo", substituted only with one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0064] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and bases and organic acids and bases. Some examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0065] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0066] Unless otherwise stated, structures depicted herein are also intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric (or conformational) forms) of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including the replacement of hydrogen with deuterium or tritium or the replacement of carbon with an enriched 13 C or 14 Compounds having the structure of the present invention at a carbon atom of the present invention are within the scope of the present invention. Such compounds can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. In certain embodiments, the R x Contains one or more deuterium atoms.

[0067] The compounds of the present invention can be connected to a detectable portion. It should be understood that such compounds can be used as imaging agents. Those of ordinary skill in the art will recognize that the detectable portion can be connected to the provided compound by a suitable substituent. As used herein, the term "suitable substituent" refers to a portion that can be covalently linked to a detectable portion. Such a portion is well known to those of ordinary skill in the art and includes groups containing, for example, a carboxylic acid portion, an amino portion, a thiol portion, or a hydroxyl portion. It will be understood that such a portion can be directly or through a linking group (e.g., a divalent saturated or unsaturated hydrocarbon chain) connected to the provided compound. In some embodiments, such a portion can be connected by click chemistry. In some embodiments, these portions can optionally be connected by 1,3-cycloaddition of an azide and an alkyne in the presence of a copper catalyst. Methods using click chemistry are known in the art and include Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41 , 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17 , those described in 52-57.

[0068] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety capable of being detected, such as primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, 32 P. 33 P. 35 S or14 C) Mass tags and fluorescent labels are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0069] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate to produce a detectable signal. For biotin, the second intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the second intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group during a non-radiative fluorescence resonance energy transfer (FRET) process, and the second group produces the detected signal.

[0070] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to, Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarins, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarins, IR dyes (IRD40, IRD 700, IRD 800), JOE, Lissamine Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetrabromosulfone-fluorescein, tetramethylrhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0071] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Some examples of mass tags include electrophoretically releasable tags, such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceryl]isopiperidic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone, and derivatives thereof. The synthesis and use of these mass tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of various lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. Various neutral and charged organic molecules (biomolecules or synthetic compounds) in the appropriate mass range (100 to 2000 Daltons) can also be used as mass tags.

[0072] Listed below are tumor-associated cell surface antigen polypeptides, ie, tumor-associated antigens (TAAs), that allow for the specific targeting of cancer cells for destruction.

[0073] TAAs include, but are not limited to, 5T4, AOC3, ALK, AXL, C242, CA-125, CCL11, CCR 5, CD2, CD3, CD4, CD5, CD15, CA15-3, CD18, CD19, CA19-9, CD20, CD22, CD23, CD25, CD28, CD30, CD31, CD33, CD37, CD38, CD40, CD41, CD44, CD44 v6, CD51, CD52, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD74, CD79-B, CD80, CD125, CD138, CD141, CD147, CD152, CD154, C D326, CEA, CTLA-4, CXCR2, EGFR, ErbB2, ErbB3, EpCAM, EphA2, EphB2, EphB4, FGFR (i.e., FGFR1, FGFR2, FGFR3, FGFR4), FLT3, Ye Acid receptor, FAP, GD2, GD3, GPNMB, HGF, HER2, ICAM, IGF-1 receptor, VEGFR1, TRPV1, CFTR, gpNMB, CA9, Cripto, c-KIT, c-MET, ACE, APP, adrenergic receptor β2, claudin 3 (Claudine3), mesothelin, MUC1, RON, ROR1, PD-L1, PD-L2, B7-H3, B7-B4, IL-2 receptor, IL-4 receptor, IL-13 receptor, integrin (including α4, α v β3, α v β5, α v β6, α1β4, α4β1, α4β7, α5β1, α6β4, α IIbβ3 integrin), IFN-α, IFN-γ, IgE, IGF-1 receptor, IL-1, IL-12, IL-23, IL-13, IL-22, IL-4, IL-5, IL-6, interferon receptor, ITGB2 (CD18), LFA-1 (CD11a), L-selectin (CD62L), mucin, MUC1, myostatin, NCA-90, NGF, PDGFRα, phosphatidylserine, prostate cancer cells, prostate-specific membrane antigen (PSMA), RANKL, Rhesus factor, SLAMF7, sphingosine-1-phosphate, TAG-72, T cell receptor, tenascin C, TGF-1, TGF-β2, TGF-β, TNF-α, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGFA, VEGFR2, vimentin, etc.

[0074] In some embodiments, the tumor-associated antigen is a carbohydrate or comprises a carbohydrate. In some embodiments, the TBT provided targets such TAAs. In some embodiments, the carbohydrate is part of a glycoprotein. In some embodiments, the carbohydrate is part of a glycolipid. Many conditions, disorders and diseases (e.g., various types of cancer) are associated with abnormal glycosylation. Tumor-associated carbohydrate antigens (TACAs) include and / or are associated with: changes in sialic acid expression, changes in Lewis carbohydrate antigen expression, changes in ganglioside expression, etc. The TBT of the present disclosure can target various types of TACAs, including those described in the art, for example, in Chua and Durrant, Monoclonal Antibodies Against Tumour-Associated Carbohydrate Antigens, Carbohydrate Mahmut Caliskan, Intech Open, DOI: 10.5772 / 66996.

[0075] Alternatively, TBT may be a high affinity binding moiety to one or more tumor-associated antigens or cell surface receptors selected from (1) to (36):

[0076] (1) BMPR1B (bone morphogenetic protein receptor-type IB, Genbank accession number NM.sub.--001203);

[0077] (2) E16 (LAT1, SLC7A5, Genbank accession number NM.sub.--003486);

[0078] (3) STEAP1 (six transmembrane epithelial antigen of prostate, Genbank accession number NM.sub.--012449);

[0079] (4) 0772P (CA125, MUC16, Genbank accession number AF361486);

[0080] (5) MPF (MPF, MSLN, SMR, megakaryocyte enhancer factor, mesothelin, Genbank accession number NM.sub.-005823);

[0081] (6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate) member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession number NM.sub.--006424);

[0082] (7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accession number AB040878);

[0083] (8) PSCA hlg (2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession number AY358628);

[0084] (9) ETBR (endothelin type B receptor, Genbank accession number AY275463);

[0085] (10) MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession number NM.sub.--017763);

[0086] (11) STEAP2 (HGNC.sub.--8639, IPCA-1, PCANAP1, STAMPI, STEAP2, STMP, prostate cancer-associated gene 1, prostate cancer-associated protein 1, prostate six-transmembrane epithelial antigen 2, six-transmembrane prostate protein, Genbank accession number AF455138);

[0087] (12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M member 4, Genbank accession number NM.sub.--017636);

[0088] (13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession number NP.sub.--003203 or NM.sub.--003212);

[0089] (14) CD21 (CR2 (complement receptor 2) or C3DR (C3d / Epstein-Barr virus receptor) or Hs.73792, Genbank accession number M26004);

[0090] (15) CD79b (CD79B, CD79β, IGb (immunoglobulin-related β), B29, Genbank accession number NM.sub.--000626);

[0091] (16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain-containing phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession number NM.sub.--030764);

[0092] (17) HER2 (Genbank accession number M1730);

[0093] (18) NCA (Genbank accession number M18728);

[0094] (19) MDP (Genbank accession number BC017023);

[0095] (20) IL20Rα (Genbank accession number AF184971);

[0096] (21) Brevican (Genbank accession number AF229053;

[0097] (22) EphB2R (Genbank accession number NM.sub.--004442);

[0098] (23) ASLG659 (Genbank accession number AX092328);

[0099] (24) PSCA (Genbank accession number AJ297436);

[0100] (25) GEDA (Genbank accession number AY260763;

[0101] (26) BAFF--R (B cell activating factor receptor, BLyS receptor 3, BR3, NP.sub.--443177.1);

[0102] (27) CD22 (B cell receptor CD22-B isoform, NP.sub.--001762.1);

[0103] (28) CD79a (CD79A, CD79α, immunoglobulin-associated α, a B cell-specific protein that covalently interacts with Igβ (CD79B) and forms a complex with Ig M molecules on the surface, transducing signals involved in B cell differentiation, Genbank accession number NP.sub.--001774.1);

[0104] (29) CXCR5 (Burkitt's lymphoma receptor 1), a G protein-coupled receptor activated by the CXCL13 chemokine, which plays a role in lymphocyte migration and humoral defense, in HIV-2 infection and possibly in the development of AIDS, lymphoma, myeloma, and leukemia, Genbank accession number NP.sub.--001707.1);

[0105] (30) HLA-DOB (β subunit of MHC class II molecule (Ia antigen), which binds to peptides and presents them to CD4 + T lymphocytes, Genbank accession number NP.sub.--002111.1);

[0106] (31) P2X5 (purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, which can participate in synaptic transmission and neurogenesis, and its deficiency can lead to the pathophysiology of idiopathic detrusor instability, Genbank accession number NP.sub.--002552.2);

[0107] (32) CD72 (B cell differentiation antigen CD72, Lyb-2, Genbank accession number NP.sub.--001773.1);

[0108] (33) LY64 (lymphocyte antigen 64 (RP105), a type I membrane protein of the leucine-rich repeat (LRR) family that regulates B cell activation and apoptosis, and loss of function is associated with increased disease activity in patients with systemic lupus erythematosus, Genbank accession number NP.sub.--005573.1);

[0109] (34) FcRH1 (Fc receptor-like protein 1, a putative receptor for immunoglobulin Fc domains containing C2-type Ig-like and ITAM domains, which may play a role in B lymphocyte differentiation, Genbank accession number NP.sub.--443170.1);

[0110] (35) IRTA2 (immunoglobulin superfamily receptor translocation-associated 2, a putative immune receptor that may have a role in B-cell development and lymphomagenesis; dysregulation of this gene by translocation occurs in some B-cell malignancies, Genbank accession number NP.sub.--112571.1); and

[0111] (36) TENB2 (putative transmembrane proteoglycan, related to the EGF / helix growth factor family and follistatin, Genbank accession number AF 179274). 3. Description of exemplary embodiments:

[0112] In certain embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof: in: ABT is the antibody binding portion; L is a divalent linker moiety connecting ABT to TBT; and TBT is the target binding moiety

[0113] In some embodiments, the present disclosure provides a compound of Formula Ia or a salt thereof. In some embodiments, the present disclosure provides a compound of Formula Ib or a salt thereof.

[0114] In certain embodiments, the present invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof, wherein: R 1 、R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from: C 1-6aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R 1 and R 1’ optionally together with its intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3’ optionally together with its intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R attached to the same carbon atom 5 Group and R 5’ The group optionally forms, together with its intervening carbon atom, a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or Two R's 5 The group optionally forms a C 1-10 A divalent linear or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -C(O)-. 1 -replace, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1’ 、R 3’ and R 5’ are each independently hydrogen or C 1-3 aliphatic; R 2 、R 4 and R 6 are each independently hydrogen or C 1-4 Aliphatic, or: R 2 and R 1optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 6 Group and its adjacent R 5 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; L 1 It will a connected trivalent linker moiety; L 2 Is a covalent bond or C 1-10 A divalent linear or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 -replace, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; TBT is a target binding moiety; and m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0115] In certain embodiments, the present invention provides a compound of formula III or a pharmaceutically acceptable salt thereof: in: Each R 7 is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R attached to the same carbon atom 7 Group and R 7'The group optionally forms, together with its intervening carbon atom, a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; Each R 7 ' are independently hydrogen or C 1-3 aliphatic; Each R 8 are independently hydrogen or C 1-4 Aliphatic, or: R 8 Group and its adjacent R 7 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 9 It is hydrogen, C 1-3 Aliphatic, or -C(O)C 1-3 aliphatic; L 3 It will a divalent linker moiety connected to TBT; TBT is a target binding moiety; and o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Antibody binding portion

[0116] The present disclosure particularly provides a medicament comprising a universal antibody binding portion, which can be combined with antibodies having different Fab regions and different specificities. In some embodiments, the antibody binding portion of the present disclosure is a universal antibody binding portion that is combined with an Fc region. In some embodiments, the combination of the universal antibody binding portion with the Fc region can occur simultaneously with the combination of an Fc receptor (e.g., CD16a) with the same Fc region (e.g., at different positions / amino acid residues in the same Fc region). In some embodiments, after the universal antibody binding portion (e.g., those in the provided medicament, compound, method, etc.) is combined, the Fc region can still interact with the Fc receptor and perform one or more or all of its immunological activities, including recruiting immune cells (e.g., effector cells, e.g., NK cells) and / or triggering, generating, promoting and / or enhancing immune system activity against target cells, tissues, objects, and / or entities, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and / or ADCP.

[0117] A variety of universal antibody binding portions may be utilized in accordance with the present disclosure. The present disclosure provides, among other things, techniques for identifying and / or evaluating universal antibody binding portions and their utilization in ARMs, such as those described in the Examples. One skilled in the art will appreciate that other techniques in the art may be suitable for identifying and / or evaluating universal antibody binding portions suitable for use in ARMs in accordance with the present disclosure. In some embodiments, the universal antibody binding portion comprises one or more amino acid residues, each of which is independently natural or non-natural. In some embodiments, the universal antibody binding portion has or a structure in the form of a salt thereof. In some embodiments, the universal antibody binding portion has In some embodiments, the universal antibody binding portion is or comprises a peptide portion, e.g., having R c -(Xaa)z- structure. In some embodiments, the universal antibody binding moiety is or comprises a cyclic peptide moiety, e.g., having In some embodiments, the universal antibody binding portion is R c -(Xaa)z- or and is a peptide unit or comprises a peptide unit. In some embodiments, -(Xaa)z- is a peptide unit or comprises a peptide unit. In some embodiments, the peptide unit comprises an amino acid residue having a positively charged side chain, such as a residue of an amino acid of Formula AI (e.g., at a physiological pH of about 7.4, a "positively charged amino acid residue," Xaa P ). In some embodiments, the Peptide unit comprises R. In some embodiments, at least one Xaa is R. In some embodiments, the Peptide unit is APAR or comprises APAR. In some embodiments, the Peptide unit is RAPA or comprises RAPA. In some embodiments, the Peptide unit comprises an amino acid residue having a side chain comprising an aromatic group, such as a residue of an amino acid of Formula AI ("aromatic amino acid residue", Xaa A In some embodiments, the peptide unit comprises a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit comprises W. In some embodiments, the peptide unit comprises a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit is or comprises Xaa A XaaXaa P Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P XaaXaa A In some embodiments, the peptide unit is or comprises Xaa P Xaa A Xaa PIn some embodiments, the peptide unit is or comprises two or more Xaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa A Xaa P XaaXaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P Xaa A Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P Xaa P Xaa A In some embodiments, the peptide unit is or comprises two or more Xaa A Xaa A Xaa F . In some embodiments, the peptide residue comprises one or more proline residues. In some embodiments, the peptide unit is or comprises HWRGWA. In some embodiments, the peptide unit is WGRR or comprises WGRR. In some embodiments, the peptide unit is RRGW or comprises RRGW. In some embodiments, the peptide unit is or comprises NRFRGKYK. In some embodiments, the peptide unit is or comprises NARKFYK. In some embodiments, the peptide unit comprises positively charged amino acid residues, aromatic amino acid residues, and amino acid residues having negatively charged side chains, such as residues of amino acids of formula AI (e.g., at physiological pH of about 7.4, "negatively charged amino acid residues," Xaa N ). In some embodiments, the peptide residue is RHRFNKD. In some embodiments, the peptide unit is TY. In some embodiments, the peptide unit is TYK. In some embodiments, the peptide unit is RTY. In some embodiments, the peptide unit is RTYK. In some embodiments, the peptide unit is or comprises a sequence selected from PAM. In some embodiments, the peptide unit is WHL. In some embodiments, the peptide unit is ELVW. In some embodiments, the peptide unit is or comprises a sequence selected from AWHLGELVW. In some embodiments, the peptide unit is or comprises a sequence selected from DCAWHLGELVWCT, the two cysteine ​​residues of which can form a disulfide bond, as found in natural proteins. In some embodiments, the peptide unit is or comprises a sequence selected from Fc-III. In some embodiments, the peptide unit is or comprises a sequence selected from DpLp AWHLGELVWIn some embodiments, the peptide unit is or comprises a sequence selected from FcBP-1. In some embodiments, the peptide unit is or comprises a sequence selected from DpLpDCAWHLGELVWCT. In some embodiments, the peptide unit is or comprises a sequence selected from FcBP-2. In some embodiments, the peptide unit is or comprises a sequence selected from CDCAWHLGELVWCTC, wherein the first and last cysteines, as well as the two cysteines in the middle of the sequence, can each independently form a disulfide bond, as in a native protein. In some embodiments, the peptide unit is or comprises a sequence selected from Fc-III-4c. In some embodiments, the peptide unit is or comprises a sequence selected from FcRM. In some embodiments, the peptide unit is or comprises a cyclic peptide unit. In some embodiments, the cyclic peptide unit comprises an amide group formed by an amino group of a side chain and a -COOH group at the C-terminus.

[0118] In some embodiments, -(Xaa)z- is or comprises [X 1 ] p1 [X 2 ] p2 -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -[X 13 ] p13 -[X 14 ] p14 [X 15 ] p15 [X 16 ] p16 , where X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 and X 13 Each is independently an amino acid residue, such as an amino acid residue of Formula AI, and p1, p2, p13, p14, p15, and p16 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, X 1 、X 2 、X 3 、X4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 and X 13 Each independently is an amino acid residue of an amino acid of formula AI. In some embodiments, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 and X 13 Each independently is a natural amino acid residue. In some embodiments, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 and X 13 wherein one or more of the residues is independently a non-natural amino acid residue as described in the present disclosure.

[0119] In some embodiments, the peptide unit includes a functional group that can react with the functional group of another amino acid residue in the amino acid residue. In some embodiments, the peptide unit includes an amino acid residue with a side chain, and the side chain includes a functional group that can react with another functional group of the side chain of another amino acid residue to form a linker (linkage) (for example, see the compound in Table 1). In some embodiments, a functional group of an amino acid residue is connected to the functional group of another amino acid residue to form a linker (or bridge). The linker is bonded to the backbone atoms of the peptide unit and does not include backbone atoms. In some embodiments, the peptide unit includes a linker formed by two side chains of non-adjacent amino acid residues. In some embodiments, the linker is bonded to two backbone atoms of two non-adjacent amino acid residues. In some embodiments, the two backbone atoms bonded to the linker are carbon atoms. In some embodiments, the linker has the structure of Lb, wherein Lb is L as described in the present disclosure. a , where La In some embodiments, L a Contains -Cy-. In some embodiments, L a Contains -Cy-, wherein -Cy- is optionally substituted heteroaryl. In some embodiments, -Cy- is In some embodiments, L a yes In some embodiments, such L a It can be formed by the -N3 group of the side chain of one amino acid residue and the -≡- of the side chain of another amino acid residue. In some embodiments, the linker is formed by the connection of two thiol groups (e.g., of two cysteine ​​residues). In some embodiments, L a Contains -SS-. In some embodiments, L a In some embodiments, the linker is formed by the connection of an amino group (e.g., -NH2 in the side chain of a lysine residue) and a carboxylic acid group (e.g., -COOH in the side chain of an aspartic acid or glutamic acid residue). a Contains -C(O)-N(R')-. In some embodiments, L a Contains -C(O)-NH-. In some embodiments, L a is -CH2CONH-(CH2)3-. In some embodiments, L a Contains -C(O)-N(R')-, wherein R' is R, and together with the R groups on the peptide backbone form a ring (eg, in 1-27). In some embodiments, L a In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene. In some embodiments, L a yes In some embodiments, L a yes In some embodiments, L a is an optionally substituted divalent C 2-20 In some embodiments, L a is optionally substituted -(CH2)9-CH=CH-(CH2)9-. In some embodiments, L a It is -(CH2)3-CH=CH-(CH2)3-.

[0120] In some embodiments, the two amino acid residues bonded to the linker are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more than 15 amino acid residues between them (excluding the two amino acid residues bonded to the linker). In some embodiments, the number is 1. In some embodiments, the number is 2. In some embodiments, the number is 3. In some embodiments, the number is 4. In some embodiments, the number is 5. In some embodiments, the number is 6. In some embodiments, the number is 7. In some embodiments, the number is 8. In some embodiments, the number is 9. In some embodiments, the number is 10. In some embodiments, the number is 11. In some embodiments, the number is 12. In some embodiments, the number is 13. In some embodiments, the number is 14. In some embodiments, the number is 15.

[0121] In some embodiments, each of p1, p2, p13, p14, p15, and p16 is 0. In some embodiments, -(Xaa)z- is or comprises -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -,in: X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue; X 6 It's Xaa A or Xaa P ; X 9 It's Xaa N ;and X 12 It's Xaa A or Xaa P . In some embodiments, X 3 、X 4 、X 5 、X 6 、X 7 、X 8、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue of an amino acid of formula AI as described in the present disclosure. In some embodiments, X 5 It's Xaa A or Xaa P In some embodiments, X 5 It's Xaa A In some embodiments, X 5 It's Xaa P In some embodiments, X 5 is an amino acid residue whose side chain comprises an optionally substituted saturated, partially saturated or aromatic ring. In some embodiments, X 5 yes In some embodiments, X 5 yes In some embodiments, X 6 It's Xaa A In some embodiments, X 6 It's Xaa P In some embodiments, X 6 In some embodiments, X 12 It's Xaa A In some embodiments, X 12 It's Xaa P In some embodiments, X 9 is Asp. In some embodiments, X 9 In some embodiments, X 12 yes In some embodiments, X 12 yes In some embodiments, X 7 、X 10 and X 11 Each is independently an amino acid residue having a hydrophobic side chain ("hydrophobic amino acid residue", Xaa H ). In some embodiments, X 7 It's Xaa H In some embodiments, X 7 yes In some embodiments, X 7 Is Val. In some embodiments, X 10 It's Xaa H In some embodiments, X 10 In some embodiments, X 10 yes In some embodiments, X 11 It's Xaa H In some embodiments, X 11 yes In some embodiments, X 8 In some embodiments, X 4 In some embodiments, X 3 In some embodiments, X 12 -COOH and Lys(X 3 ) forms an amide bond with the side chain amino group of Lys(X 3 ) is linked to a linker moiety and then to a target binding moiety.

[0122] In some embodiments, -(Xaa)z- is or comprises -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -,in: X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue; At least two amino acid residues are linked by one or more linkers L b connect; L b is optionally substituted and selected from C1-C 20 aliphatic or C1-C ... 20 a heteroaliphatic divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-, wherein L bis bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue, and does not contain a backbone atom; X 6 It's Xaa A or Xaa P ; X 9 It's Xaa N ;and X 12 It's Xaa A or Xaa P . In some embodiments, X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue of an amino acid of formula AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b In some embodiments, X 5 and X 10 By L b In some embodiments, there is one linker L b In some embodiments, X 6 It's Xaa A In some embodiments, X 6 It's Xaa P In some embodiments, X 6 In some embodiments, X 9 is Asp. In some embodiments, X 9 In some embodiments, X 12 It's Xaa A In some embodiments, X 12 yes In some embodiments, X 12 yes In some embodiments, X 12 yes In some embodiments, X 4 、X 7 and X 11 Each is independently Xaa H In some embodiments, X 4 It's Xaa H In some embodiments, X 4is Ala. In some embodiments, X 7 It's Xaa H In some embodiments, X 7 yes In some embodiments, X 11 It's Xaa H In some embodiments, X 11 yes In some embodiments, X 8 In some embodiments, X 3 In some embodiments, X 12 -COOH and Lys(X 3 ) forms an amide bond with the side chain amino group of Lys(X 3 ) is connected to a linker moiety and then to a target binding moiety. In some embodiments, L b yes In some embodiments, L b yes In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 5 and X 10 Both are Cys, and the two -SH groups of their side chains form -SS-(L b is -CH2-SS-CH2-).

[0123] In some embodiments, -(Xaa)z- is or comprises -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -,in: X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue; At least two amino acid residues are linked by one or more linkers L b connect; Lb is optionally substituted and selected from C1-C 20 aliphatic or C1-C ... 20 a heteroaliphatic divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-, wherein L b is bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue, and does not contain a backbone atom; X 4 It's Xaa A ; X 5 It's Xaa A or Xaa P ; X 8 It's Xaa N ;and X 11 It's Xaa A . In some embodiments, X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue of an amino acid of formula AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b In some embodiments, there is one linker L b In some embodiments, X 2 and X 12 By L b In some embodiments, L b Is -CH2-SS-CH2-. In some embodiments, L b Is -CH2-CH2-S-CH2-. In some embodiments, L b yes In some embodiments, L b yes In some embodiments, L b In some embodiments, R' and the R groups on the backbone atoms bonded to -N(R')-CH2CH2- form a ring, for example, as in I-27. In some embodiments, the ring formed is 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered. In some embodiments, the ring formed is monocyclic. In some embodiments, the ring formed is saturated. In some embodiments, L b yes In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 4 It's Xaa A In some embodiments, X 4 In some embodiments, X 5 It's Xaa A In some embodiments, X 5 It's Xaa P In some embodiments, X 5 In some embodiments, X 8 is Asp. In some embodiments, X 8 It's Glu. X 11 In some embodiments, X 2 and X 12 Both are Cys, and the two -SH groups of their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, X 3 、X 6 、X 9 and X 10 Each is independently Xaa H In some embodiments, X 3 It's Xaa H In some embodiments, X 3 is Ala. In some embodiments, X 6 It's Xaa H In some embodiments, X 6 In some embodiments, X 9 It's Xaa H In some embodiments, X 9 In some embodiments, X 9 yes In some embodiments, X 10 It's Xaa H In some embodiments, X10 Is Val. In some embodiments, X 10 yes In some embodiments, X 7 In some embodiments, p1 is 1. In some embodiments, X 1 is Asp. In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X 13 is an amino acid residue containing a polar uncharged side chain (e.g., at physiological pH, a "polar uncharged amino acid residue," Xaa L ). In some embodiments, X 13 is Val. In some embodiments, p13 is O. In some embodiments, Rc is -NHCH2CH(OH)CH3. In some embodiments, R c is (R)-NHCH2CH(OH)CH3. In some embodiments, Rc is (S)-NHCH2CH(OH)CH3.

[0124] In some embodiments, -(Xaa)z- is or comprises -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 _, in: X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue; At least two amino acid residues are linked by one or more linkers L b connect; L b is optionally substituted and selected from C1-C 20 aliphatic or C1-C ... 20a heteroaliphatic divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-, wherein L b is bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue, and does not contain a backbone atom; X 5 It's Xaa A or Xaa P ; X 8 It's Xaa N ;and X 11 It's Xaa A . In some embodiments, X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue of an amino acid of formula AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b In some embodiments, there is one linker L b In some embodiments, there are two or more linkers L b In some embodiments, there are two linkers L b In some embodiments, X 2 and X 12 By L b In some embodiments, X 4 and X 9 By L b In some embodiments, X 4 and X 10 By L b In some embodiments, L b Is -CH2-SS-CH2-. In some embodiments, L b yes In some embodiments, Lb yes In some embodiments, X 2 and X 12 Both are Cys, and the two -SH groups of their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, X 4 and X 10 Both are Cys, and the two -SH groups of their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, X 4 and X 9 By L b Connection, where L b yes In some embodiments, X 4 and X 9 By L b Connection, where L b yes In some embodiments, X 5 It's Xaa A In some embodiments, X 5 It's Xaa P In some embodiments, X 5 In some embodiments, X 8 is Asp. In some embodiments, X 8 In some embodiments, X 11 In some embodiments, X 11 yes In some embodiments, X 2 and X 12 Connected via Lb, where L b Is -CH2-S-CH2CH2-. In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 3 、X 6 and X 9 Each is independently Xaa H In some embodiments, X 3 It's Xaa H In some embodiments, X 3 is Ala. In some embodiments, X 6 It's Xaa H In some embodiments, X 6 In some embodiments, X 6 yes In some embodiments, X 9 It's Xaa H In some embodiments, X 9 In some embodiments, X 9 yes In some embodiments, X 10 It's Xaa H In some embodiments, X 10 Is Val. In some embodiments, X 7 In some embodiments, p1 is 1. In some embodiments, X 1 It's Xaa N In some embodiments, X 1 is Asp. In some embodiments, X 1 is Glu. In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X 13 It's Xaa L In some embodiments, X 13 It's Val.

[0125] In some embodiments, -(Xaa)z- is or comprises -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 -,in: X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 、X 14 、X 15 and X 16 Each is independently an amino acid residue; At least two amino acid residues are linked by a linker L b connect; L b is optionally substituted and selected from C1-C 20 aliphatic or C1-C ... 20 a heteroaliphatic divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-, wherein L b is bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue, and does not contain a backbone atom; X 3 It's Xaa N ; X 6 It's Xaa A ; X 7 It's Xaa A or Xaa P ; X 9 It's Xaa N ;and X 13 It's Xaa A . In some embodiments, X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 Each is independently an amino acid residue of an amino acid of formula AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are linked by L b In some embodiments, there is one linker L b In some embodiments, there are two or more linkers L b In some embodiments, there are two linkers L b In some embodiments, X 2 By L b With X 16 In some embodiments, X 4 By L bWith X 14 In some embodiments, X 2 and X 16 Both are Cys, and the two -SH groups of their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, X 4 and X 14 Both are Cys, and the two -SH groups of their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 3 is Asp. In some embodiments, X 3 In some embodiments, X 5 It's Xaa H In some embodiments, X 5 is Ala. In some embodiments, X 6 It's Xaa A In some embodiments, X 6 In some embodiments, X 7 It's Xaa A In some embodiments, X 7 It's Xaa P In some embodiments, X 7 In some embodiments, X 8 It's Xaa H In some embodiments, X 8 is Ala. In some embodiments, X 9 In some embodiments, X 10 is Asp. In some embodiments, X 10 In some embodiments, X 11 It's Xaa H In some embodiments, X 11 In some embodiments, X 12 It's Xaa H In some embodiments, X 12 Is Val. In some embodiments, X 13 It's Xaa A In some embodiments, X 13 In some embodiments, X 15 are amino acid residues containing polar uncharged side chains (e.g., at physiological pH, "Polar uncharged amino acid residue", Xaa L ). In some embodiments, X 15 Is Val. In some embodiments, p1 is 1. In some embodiments, In some embodiments, X 1 It's Xaa N In some embodiments, X 1 is Asp. In some embodiments, X 1 It's Glu.

[0126] As will be appreciated by those skilled in the art, an amino acid residue may be replaced with another amino acid residue having similar properties, e.g., an Xaa H (e.g. Val, Leu, etc.) can be replaced by another Xaa H (e.g. Leu, Ile, Ala, etc.), one Xaa A Can be replaced by another Xaa A , an Xaa P Can be replaced by another Xaa P , an Xaa N Can be replaced by another Xaa N , an Xaa L Can be replaced by another Xaa L ,wait.

[0127] In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) is a universal antibody binding portion of the compounds in Table 1. In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) is or comprises optionally substituted:

[0128] In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-1. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-2. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-3. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-4. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-5. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-6. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-7. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-8. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-9. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-10. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-11. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-12. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-13. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-14. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-15. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-16. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-17. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-18. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-19. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-20. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-21. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-22. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-23. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-24. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-25. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-26. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-27. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-28. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-29. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-30.In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-31. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-32. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-33. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-34. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-35. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-36. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-37. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-38. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-39. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-40. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-41. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-42. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-43. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-44. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-45. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-46. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-47. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-48. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-49. In some embodiments, it is unsubstituted. In some embodiments, it is substituted.

[0129] In some embodiments, the universal antibody binding portion comprises a peptide unit and is connected to a linker portion via the C-terminus of the peptide unit. In some embodiments, it is connected to a linker portion via the N-terminus of the peptide unit. In some embodiments, it is connected via a side chain group of the peptide unit.

[0130] In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) is or comprises a small molecule entity having a molecular weight of, for example, less than 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, etc. Suitable such antibody binding portions include small molecule Fc binder portions, such as those described in US 9,745,339, US20130131321, etc.

[0131] As will be appreciated by those skilled in the art, antibodies with different properties and activities (e.g., antibodies that recognize different antigens, have optional modifications, etc.) can be raised by the antibody binding moieties described in the present disclosure. In some embodiments, such antibodies include, for example, antibodies administered to a subject for therapeutic purposes. In some embodiments, the antibodies raised by the antibody binding moiety comprise antibodies against different antigens. In some embodiments, the antibodies raised by the antibody binding moiety comprise antibodies whose antigens are not present on the surface or cell membrane of a target cell (e.g., a target cell, such as a cancer cell). In some embodiments, the antibodies raised by the antibody binding moiety comprise antibodies that do not target an antigen present on the surface or cell membrane of a target cell (e.g., a target cell, such as a cancer cell). In some embodiments, the antigens on the target cell surface can interfere with the structure, conformation, and / or one or more properties and / or activity of the raised antibodies that bind to such antigens. In some embodiments, as will be appreciated by those skilled in the art, the provided technology comprises universal antibody binding moieties that recruit antibodies of different specificities, with no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% percentage of the recruited antibodies being directed against the same antigen, protein, lipid, carbohydrate, etc. One advantage of the present disclosure, among other things, is that the provided technology (comprising universal antibody binding moieties) can utilize a variety of antibody repertoires, such as those present in serum. In some embodiments, the universal antibody binding portions of the present disclosure (e.g., those in ARM) are contacted with a plurality of antibodies, wherein no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% percent of the plurality of antibodies are directed against the same antigen, protein, lipid, carbohydrate, etc. amino acids

[0132] In some embodiments, provided compounds and agents may comprise one or more amino acid moieties, for example, in universal antibody binding moieties, linker moieties, and the like. The amino acid moieties may be those of natural amino acids or non-natural amino acids. In some embodiments, the amino acid has a structure of Formula AI or a salt thereof: NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -COOH AI, wherein each variable is independent as described in the present disclosure. In some embodiments, the amino acid residue has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 The structure of -CO-.

[0133] In some embodiments, L a1 In some embodiments, the compound of formula AI has the structure NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH.

[0134] In some embodiments, L a2 In some embodiments, the compound of formula AI has the structure NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH.

[0135] In some embodiments, L a1 is a covalent bond, and L a2 In some embodiments, the compound of formula AI has the structure NH(R a1 )-C(R a2 )(R a3 )-COOH.

[0136] In some embodiments, L a is a covalent bond. In some embodiments, L a is optionally substituted C 1-6 In some embodiments, L a is optionally substituted C 1-6 In some embodiments, L a In some embodiments, L a is -CH2CH2-. In some embodiments, L a It is -CH2CH2CH2-.

[0137] In some embodiments, R' is R. In some embodiments, R a1 is R, wherein R is as described in the present disclosure. In some embodiments, R a2 is R, wherein R is as described in the present disclosure. In some embodiments, R a3 is R, wherein R is as described in the present disclosure. In some embodiments, Ra1 、R a2 and R a3 Each is independently R, wherein R is as described in this disclosure.

[0138] In some embodiments, R a1 In some embodiments, R a2 In some embodiments, R a3 In some embodiments, R a1 is hydrogen, and R a2 and R a3 In some embodiments, at least one of R a1 is hydrogen, R a2 and R a3 One of the is hydrogen and the other is not hydrogen.

[0139] In some embodiments, R a2 Yes-L a -R, wherein R is as described in the present disclosure. In some embodiments, R a2 Yes-L a -R, wherein R is an optionally substituted group selected from the group consisting of: C 3-30 Cycloaliphatic, C 5-30 aryl, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. a2 Yes-L a -R, wherein R is an optionally substituted group selected from the group consisting of: C 6-30 aryl and 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R a2 is the side chain of an amino acid. a2 are the side chains of standard amino acids.

[0140] In some embodiments, R a3 Yes-L a -R, wherein R is as described in the present disclosure. In some embodiments, R a3 Yes-L a -R, wherein R is an optionally substituted group selected from the group consisting of: C 3-30 Cycloaliphatic, C 5-30 aryl, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. a3Yes-L a -R, wherein R is an optionally substituted group selected from the group consisting of: C 6-30 aryl and 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R a3 is the side chain of an amino acid. a3 are the side chains of standard amino acids.

[0141] In some embodiments, R is a cyclic group. In some embodiments, R is an optionally substituted C 3-30 Cycloaliphatic groups. In some embodiments, R is cyclopropyl.

[0142] In some embodiments, R is an aromatic group and the amino acid residue of the amino acid of formula AI is Xaa A In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-trifluoromethylphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, R is optionally substituted 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is optionally substituted 5- to 14-membered heteroaryl having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is In some embodiments, R is optionally substituted pyridinyl. In some embodiments, R is 1-pyridinyl. In some embodiments, R is 2-pyridinyl. In some embodiments, R is 3-pyridinyl. In some embodiments, R is

[0143] In some embodiments, R' is -COOH. In some embodiments, the amino acid residue of the compound of formula AI and the amino acid is Xaa N .

[0144] In some embodiments, R' is -NH2. In some embodiments, the compound of the amino acid residue of the amino acid of formula AI is Xaa P .

[0145] In some embodiments, R a2 or R a3 is R, wherein R is C as described in the present disclosure 1-20 In some embodiments, the compound of the amino acid residue of the amino acid of formula AI is Xaa HIn some embodiments, R is -CH3. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is cyclopropyl.

[0146] In some embodiments, R a1 、R a2 and R a3 Two or more of are R and together form an optionally substituted ring as described in the disclosure.

[0147] In some embodiments, R a1 and R a2 and R a3 One of them is R, and together they form an optionally substituted 3-6 membered ring, which except for R a1 There are no other ring heteroatoms besides the bonded nitrogen atom.In some embodiments, the ring formed is a 5-membered ring as in proline.

[0148] In some embodiments, R a2 and R a3 is R, and together form an optionally substituted 3-6 membered ring as described in the present disclosure. In some embodiments, R a2 and R a3 is R, and together form an optionally substituted 3-6 membered ring having one or more nitrogen ring atoms. a2 and R a3 is R, and together form an optionally substituted 3-6 membered ring having one and no more than one ring heteroatom that is a nitrogen atom. In some embodiments, the ring is a saturated ring.

[0149] In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is an unnatural amino acid. In some embodiments, the amino acid is an α-amino acid. In some embodiments, the amino acid is a β-amino acid. target

[0150] In some embodiments, the present disclosure provides techniques for selectively directing agents (e.g., ARM compounds), antibodies, and immune cells (e.g., NK cells) comprising a target binding portion to a desired target site comprising one or more targets. As will be appreciated by those skilled in the art, the techniques provided can be used for various types of targets.

[0151] In some embodiments, the target is damaged or defective tissue. In some embodiments, the target is damaged tissue. In some embodiments, the target is defective tissue. In some embodiments, the target is associated with a disease, disorder, or condition (e.g., cancer, trauma, etc.). In some embodiments, the target is a tumor. In some embodiments, the target is or comprises a diseased cell. In some embodiments, the target is or comprises a cancer cell. In some embodiments, the target is a foreign object. In some embodiments, the target is or comprises an infectious agent. In some embodiments, the target is a microorganism. In some embodiments, the target is or comprises a bacterium. In some embodiments, the target is or comprises a virus.

[0152] In many embodiments, the target is a tissue and / or cell associated with a disease, disorder or condition, particularly various types of cancer. In some embodiments, the target is or comprises a cancer cell. The present disclosure provides, among other things, techniques that are particularly useful for selectively targeting the immune system to cancer cells by, for example, using ARMs to recruit antibodies (e.g., endogenous antibodies) and immune cells.

[0153] The target site typically comprises one or more physical, chemical and / or biological markers that can be exploited, e.g., by the target binding portion of a provided compound (e.g., ARM), to selectively recruit antibodies and / or fragments thereof and / or immune cells to the target.

[0154] In some embodiments, the cells of the target site contain one or more characteristic agents that can be used for targeting. In some embodiments, such agents are proteins and / or fragments thereof. In some embodiments, such agents are antigens specifically associated with a disease, disorder, or condition.

[0155] For example, in some embodiments, cancer cells may contain one or more tumor-specific antigens or tumor-associated antigens. Target binding moieties as described in the present disclosure can selectively bind to these markers. In some embodiments, the target binding moieties of the present disclosure are small molecules that can be used to bind to cell surface proteins and / or intracellular proteins.

[0156] In some embodiments, a signature factor, e.g., a signature factor of cells of a target site, etc., is or comprises a carbohydrate, e.g., those on the surface of a cell, in a glycosylated protein, etc. In some embodiments, a signature factor is or comprises a lipid.

[0157] In some embodiments, a signature factor, such as a signature factor of cells at a target site, is extracellular. In some embodiments, a signature factor is an extracellular protein. In some embodiments, a signature factor is on the surface of a cell. In some embodiments, a signature factor is a protein present on the surface of a cell. For example, in many tumor tissues, cell surface and / or extracellular mucins exhibit different glycosylation levels and / or patterns and can be used for targeting.

[0158] In some embodiments, the target site (e.g., diseased tissue, etc.) has one or more physical, biological, and / or chemical properties that can be exploited by the target binding moiety. In some embodiments, such a property is pH. In some embodiments, such a property is the concentration of one or more chemical substances. For example, the tumor microenvironment is typically hypoxic and / or acidic (e.g., pH 6.5-6.9 vs. 7.2-7.4).

[0159] In some embodiments, the target is or comprises a peptide or a fragment thereof. In some embodiments, the target is or comprises a protein or a fragment thereof. In some embodiments, the target is avidin. In some embodiments, the target is streptavidin. In some embodiments, the target is or comprises an antigen. In some embodiments, the target is or comprises a tumor-specific antigen. In some embodiments, the target is or comprises a tumor-associated antigen.

[0160] In some embodiments, the target is or comprises a nucleic acid.

[0161] In some embodiments, the target is or comprises a lipid.

[0162] In some embodiments, the target is or comprises a carbohydrate. In some embodiments, the target is or comprises a carbohydrate associated with a disease, disorder, or condition. In some embodiments, the target is or comprises a carbohydrate associated with cancer, such as a carbohydrate that is a glycan modification of a protein, such as on the surface of a cancer cell or outside of the cell. Target binding moiety

[0163] In accordance with the present disclosure, various types and chemical classes of target binding moieties may be utilized, and in accordance with the present disclosure, various techniques for identifying and / or evaluating the properties of target binding moieties (e.g., assays, reagents, kits, etc.) may be utilized. Generally speaking, a target binding moiety interacts with a target site through one or more physical, biological, and / or chemical properties. In some embodiments, the target binding moiety binds to a characteristic factor described in the present disclosure. In some embodiments, the target binding moiety binds to surface, extracellular, and / or intracellular proteins, carbohydrates, and / or nucleic acids. In some embodiments, the target binding moiety binds to a surface protein of a target cell. In some embodiments, the target binding moiety is a small molecule moiety. In some embodiments, the target binding moiety is an antibody agent. In some embodiments, the target binding moiety is a nucleic acid agent, such as an aptamer. In some embodiments, the target binding moiety is a lipid moiety. Certain types of target binding moieties are described below; those skilled in the art will appreciate that other types of target binding moieties, including many known in the art, may also be used in accordance with the present disclosure.

[0164] In some embodiments, the target binding moiety binds to the target through one or more proteins, lipids, nucleic acids, carbohydrates, small molecules, etc. of the target. For example, in some embodiments, the target binding moiety binds to a tumor-specific antigen of the target cancer cell. In some embodiments, the tumor-specific antigen is or comprises a carbohydrate or a fragment thereof. In some embodiments, the tumor-specific antigen is or comprises a protein or a fragment thereof. a. Small molecules

[0165] In some embodiments, the target binding moiety is a small molecule moiety. In some embodiments, the molecular weight of the small molecule moiety is no greater than 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, 900, 800, 700, or 600. In some embodiments, the molecular weight of the small molecule moiety is no greater than 8000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 7000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 6000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 5000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 4000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 3000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 2000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 1500. In some embodiments, the molecular weight of the small molecule moiety is no greater than 1000. In some embodiments, the molecular weight of the small molecule moiety is no greater than 900. The present disclosure encompasses, inter alia, the recognition that small molecule target binding moieties may be capable of binding to markers on the outside, surface, and / or inside a target (eg, a cancer cell).

[0166] In some embodiments, the small molecule target binding moiety is or comprises a moiety that selectively binds to a protein or fragment thereof (e.g., a cancer antigen). For example, in some embodiments, the target binding moiety is or comprises a moiety that selectively binds to prostate specific membrane antigen (PSMA). In some embodiments, the target binding moiety is or comprises a moiety that selectively binds to

[0167] In some embodiments, the small molecule target binding moiety is or comprises a biotin moiety. In some embodiments, the small molecule target binding moiety is or comprises a In some embodiments, the small molecule target binding moiety is or comprises b. Peptide agent

[0168] In some embodiments, the target binding moiety is or comprises a peptide agent. In some embodiments, the target binding moiety is a peptide moiety. In some embodiments, the peptide moiety can be linear or cyclic. In some embodiments, the target binding moiety is or comprises a cyclic peptide moiety. A variety of peptide target binding moieties are known in the art and can be used in accordance with the present disclosure.

[0169] In some embodiments, the target binding moiety is or comprises a peptide aptamer agent. c. aptamer agent

[0170] In some embodiments, the target binding moiety is or comprises a nucleic acid agent. In some embodiments, the target binding moiety is or comprises an oligonucleotide moiety. In some embodiments, the target binding moiety is or comprises an aptamer agent. A variety of aptamer agents are known in the art or can be readily developed using common techniques and can be utilized in the technology provided according to the present disclosure. Connector

[0171] In some embodiments, the antibody binding moiety is optionally linked to the target binding moiety via a linker moiety.In accordance with the present disclosure, various types and / or linker moieties may be used, such as those used in antibody-drug conjugates, etc.

[0172] The linker moiety can be divalent or multivalent. In some embodiments, the linker moiety is divalent. In some embodiments, the linker is multivalent and connects more than two moieties.

[0173] In some embodiments, the linker moiety is L. In some embodiments, L is a covalent bond, or a divalent or multivalent optionally substituted linear or branched C 1-100 A group comprising one or more aliphatic, aromatic, heteroaliphatic having 1 to 20 heteroatoms, heteroaromatic having 1 to 20 heteroatoms, or any combination thereof, wherein one or more methylene units of the group are optionally and independently replaced by: C 1-6 Alkylene, C 1-6 Alkenylene, divalent C 1-6 Heteroaliphatic, -Cy-, -C(R')2-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S -, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR') -, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')- or -[(-OC(R')2-C(R')2-) n ]-, where n is 1 to 20.

[0174] In some embodiments, L is divalent. In some embodiments, L is divalent or optionally substituted linear or branched selected from C 1-00 aliphatic and having 1 to 50 heteroatoms C 1-100 A heteroaliphatic group wherein one or more methylene units of the group are optionally and independently replaced by: C 1-6 Alkylene, C 1-6 Alkenylene, divalent C 1-6 Heteroaliphatic, -Cy-, -C(R')2-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -C(O)C(R')2N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S -, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR') -, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')- or -[(-OC(R')2-C(R')2-) n ]-.

[0175] In some embodiments, L is a covalent bond. In some embodiments, L is a divalent optionally substituted linear or branched C 1-100 An aliphatic group wherein one or more methylene units of the group are optionally and independently replaced. In some embodiments, L is a divalent optionally substituted linear or branched C 6-100 An aryl aliphatic group wherein one or more methylene units of the group are optionally and independently replaced. In some embodiments, L is a divalent optionally substituted linear or branched C 5-100 Heteroaryl aliphatic groups, wherein one or more methylene units of the group are optionally and independently replaced. In some embodiments, L is a divalent optionally substituted linear or branched C 1-100 A heteroaliphatic group wherein one or more methylene units of the group are optionally and independently replaced.

[0176] In some embodiments, the linker moiety (e.g., L) is or comprises one or more polyethylene glycol units. In some embodiments, the linker moiety is or comprises -(CH2CH2O) n-, wherein n is as described in the present disclosure. In some embodiments, one or more methylene units of L are independently replaced by -(CH2CH2O) n In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

[0177] In some embodiments, the linker moiety comprises one or more moieties that can be used to connect to other moieties, such as amino, carbonyl, etc. In some embodiments, the linker moiety comprises one or more -NR'-, wherein R' is as described in the present disclosure. In some embodiments, -NR'- improves solubility. In some embodiments, -NR'- serves as a point of attachment to another moiety. In some embodiments, R' is -H. In some embodiments, one or more methylene units of L are independently replaced by -NR'-, wherein R' is as described in the present disclosure.

[0178] In some embodiments, the linker moiety (eg, L) comprises a -C(O)- group, which can be used to link to a moiety. In some embodiments, one or more methylene units of L are independently replaced by -C(O)-.

[0179] In some embodiments, the linker moiety is or comprises one or more ring moieties, for example, one or more methylene units of L are replaced by -Cy-. In some embodiments, the linker moiety (e.g., L) comprises an aryl ring. In some embodiments, the linker moiety (e.g., L) comprises a heteroaryl ring. In some embodiments, the linker moiety (e.g., L) comprises an aliphatic ring. In some embodiments, the linker moiety (e.g., L) comprises a heterocyclyl ring. In some embodiments, the linker moiety (e.g., L) comprises a polycyclic ring. In some embodiments, the ring in the linker moiety (e.g., L) is 3 to 20 yuan. In some embodiments, the ring is 5 yuan. In some embodiments, the ring is 6 yuan. In some embodiments, the ring in the joint is the product of a cycloaddition reaction (e.g., click chemistry and its variants) for connecting different parts together.

[0180] In some embodiments, the linker moiety (eg, L) is or comprises In some embodiments, the methylene units of L are In some embodiments, -Cy- is

[0181] In some embodiments, the linker moiety is as described in Table 1. Other linker moieties include, for example, 2 In some embodiments, L is L of the present disclosure. 1 In some embodiments, L is L as described in the present disclosure. 2 In some embodiments, L is L as described in the present disclosure. 3 In some embodiments, L is L as described in the present disclosure. b .

[0182] In some embodiments, L is Certain implementations of variables

[0183] As examples, exemplary embodiments of variables are described throughout this disclosure. As will be appreciated by those skilled in the art, the embodiments for the different variables may be optionally combined.

[0184] As defined above and described herein, an ABT is an antibody binding portion.

[0185] In some embodiments, the ABT is an antibody binding portion.

[0186] In some embodiments, the ABT is selected from those shown in Table 1 below.

[0187] As defined above and described herein, L is a divalent linker moiety that connects ABT to TBT.

[0188] In some embodiments, L is a divalent linker moiety that connects ABT to TBT.

[0189] In some embodiments, L is selected from those shown in Table 1 below.

[0190] As defined above and described herein, TBT is a target binding moiety.

[0191] In some embodiments, TBT is a target binding moiety.

[0192] In some embodiments, TBT is selected from those shown in Table 1 below.

[0193] As defined above and described herein, R 1 、R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R 1 and R 1’ optionally together with its intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3’ optionally together with its intervening carbon atom to form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R attached to the same carbon atom 5 Group and R 5’ The group optionally forms, together with its intervening carbon atom, a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R 5 The group optionally forms a C 1-10 A divalent linear or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -C(O)-. 1 -replace, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0194] In some embodiments, R 1 In some embodiments, R 1 is an optionally substituted group selected from the group consisting of: C 1-6aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8- to 10-membered bicyclic aromatic carbocycle, 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. 1 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0195] In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0196] In some embodiments, R 1 yes In some embodiments, R1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0197] In some embodiments, R 1 yes In some embodiments, R 1 yes

[0198] In some embodiments, R 1 and R 1’ and optionally together with its intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. 1 and R 1’ Optionally, together with its intervening carbon atoms, it forms a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0199] In some embodiments, R 1 Select from those shown in Table 1 below.

[0200] In some embodiments, R is as described in the present disclosure. 1 In some embodiments, R a2 is R as described in this disclosure 1 In some embodiments, R a3 is R as described in this disclosure 1 .

[0201] In some embodiments, R 3 In some embodiments, R 3 is an optionally substituted group selected from the group consisting of: C 1-6aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8- to 10-membered bicyclic aromatic carbocycle, 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 3 is optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. 3 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 3 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 3 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0202] In some embodiments, R 3 In some embodiments, R 3 yes In some embodiments, R 3 yes

[0203] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (R) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (R) stereochemistry.

[0204] In some embodiments, R 3 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (R) stereochemistry.

[0205] In some embodiments, R 3 and R 3’ and optionally together with its intervening carbon atoms form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. 3 and R 3’ Optionally, together with its intervening carbon atoms, it forms a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0206] In some embodiments, R 3 Select from those shown in Table 1 below.

[0207] In some embodiments, R is as described in the present disclosure. 2 In some embodiments, R a2 is R as described in this disclosure 2 In some embodiments, R a3 is R as described in this disclosure 2 .

[0208] In some embodiments, R 5 In some embodiments, R 5 is an optionally substituted group selected from the group consisting of: C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8- to 10-membered bicyclic aromatic carbocycle, 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is optionally substituted C 1-6 In some embodiments, R 5 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 5 is optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. 5 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0209] In some embodiments, R 5 In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 5 yes wherein the attachment site has an (R) stereochemistry. In some embodiments, R 5 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 5 yes wherein the attachment site has an (R) stereochemistry. In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0210] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0211] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0212] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0213] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 4 5 In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 4 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 4 yes wherein the attachment site has an (R) stereochemistry.

[0214] In some embodiments, R 5 and R 5’ The group optionally forms a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring together with its intervening carbon atom. In some embodiments, R 5 and R 5’The group is optionally taken together with its intervening carbon atom to form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0215] In some embodiments, both R 5 The group optionally forms a C 1-10 A divalent linear or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -C(O)-. 1 -replace, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0216] In some embodiments, both R 5 The group together with its intervening atoms forms In some embodiments, both R 5 The group together with its intervening atoms forms In some embodiments, both R 5 The group together with its intervening atoms forms In some embodiments, both R 5 The group together with its intervening atoms forms

[0217] In some embodiments, R 5 Select from those shown in Table 1 below.

[0218] In some embodiments, R is as described in the present disclosure. 5 In some embodiments, R a2 is R as described in this disclosure 5 In some embodiments, R a3 is R as described in this disclosure 5 .

[0219] As defined above and described herein, R 1’ 、R 3’ and R 5’ are each independently hydrogen or C 1-3 aliphatic.

[0220] In some embodiments, R 1’ In some embodiments, R 1’ It is C 1-3 aliphatic.

[0221] In some embodiments, R 1’ In some embodiments, R 1’ In some embodiments, R 1’ In some embodiments, R 1’ In some embodiments, R 1’ It is cyclopropyl.

[0222] In some embodiments, R 1’ Select from those shown in Table 1 below.

[0223] In some embodiments, R 3’ In some embodiments, R 3’ It is C 1-3 aliphatic.

[0224] In some embodiments, R 3’ In some embodiments, R 3’ In some embodiments, R 3’ In some embodiments, R 3’ In some embodiments, R 3’ It is cyclopropyl.

[0225] In some embodiments, R 3’ Select from those shown in Table 1 below.

[0226] In some embodiments, R 5’ In some embodiments, R 5’ It is C 1-3 aliphatic.

[0227] In some embodiments, R 5’ In some embodiments, R 5’ In some embodiments, R 5’ In some embodiments, R 5’ In some embodiments, R 5’ It is cyclopropyl.

[0228] In some embodiments, R 5’ Select from those shown in Table 1 below.

[0229] As defined above and described herein, R 2 、R 4 and R 6 are each independently hydrogen or C 1-4 Aliphatic, or: R 2 and R 1optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 6 Group and its adjacent R 5 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0230] In some embodiments, R 2 In some embodiments, R 2 It is C 1-4 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is tert-butyl.

[0231] In some embodiments, R 2 and R 1 Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0232] In some embodiments, R 2 and R 1 Together with its intervening atoms, In some embodiments, R 2 and R 1 Together with its intervening atoms,

[0233] In some embodiments, R 2 Select from those shown in Table 1 below.

[0234] In some embodiments, R 4 In some embodiments, R 4 It is C 1-4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is tert-butyl.

[0235] In some embodiments, R 4 and R 3 Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0236] In some embodiments, R 4 and R 3 Together with its intervening atoms, In some embodiments, R 4 and R 3 Together with its intervening atoms,

[0237] In some embodiments, R 4 Select from those shown in Table 1 below.

[0238] In some embodiments, R 6 In some embodiments, R 6 It is C 1-4 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 It is tert-butyl.

[0239] In some embodiments, R 6 Group and its adjacent R 5 The group, together with its intervening atoms, forms a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0240] In some embodiments, R 6 Group and its adjacent R 5 The group together with its intervening atoms forms In some embodiments, R 6 Group and its adjacent R 5 The group together with its intervening atoms forms

[0241] In some embodiments, R 6 Select from those shown in Table 1 below.

[0242] In some embodiments, R is as described in the present disclosure. 1’ In some embodiments, R a2 is R as described in this disclosure 1’ In some embodiments, R a3 is R as described in this disclosure 1’ In some embodiments, R is as described in the present disclosure. 3’ In some embodiments, R a2 is R as described in this disclosure 3’ In some embodiments, R a3 is R as described in this disclosure 3’ In some embodiments, R is as described in the present disclosure. 2 In some embodiments, R a2 is R as described in this disclosure 2 In some embodiments, R a3 is R as described in this disclosure 2 In some embodiments, R is as described in the present disclosure. 4 In some embodiments, R a2 is R as described in this disclosure 4 In some embodiments, R a3 is R as described in this disclosure 4 In some embodiments, R is as described in the present disclosure. 6 In some embodiments, R a2 is R as described in this disclosure 6 In some embodiments, R a3 is R as described in this disclosure 6 .

[0243] As defined above and described herein, L 1 It will A trivalent linker moiety is attached.

[0244] In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0245] In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0246] In some embodiments, L 1 Select from those shown in Table 1 below.

[0247] As defined above and described herein, L 2 Is a covalent bond or C 1-10 A divalent linear or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 -replace, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0248] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 It is C 1-10 A divalent linear or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 -replace, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0249] In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes

[0250] In some embodiments, L 2 Select from those shown in Table 1 below.

[0251] In some embodiments, L is L as described in the present disclosure. 2 .

[0252] As defined above and described herein, TBT is a target binding moiety.

[0253] In some embodiments, TBT is a target binding moiety.

[0254] In some embodiments, TBT is In some embodiments, TBT is

[0255] In some embodiments, TBT is selected from those shown in Table 1 below.

[0256] As defined above and described herein, m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0257] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0258] In some embodiments, m is selected from those shown in Table 1 below.

[0259] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0260] In some embodiments, n is selected from those shown in Table 1 below.

[0261] As defined above and described herein, each R 7 is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R attached to the same carbon atom 7 Group and R 7 The ' group optionally forms, together with its intervening carbon atom, a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0262] In some embodiments, R 7 In some embodiments, R 7 is an optionally substituted group selected from the group consisting of: C 1-6aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8- to 10-membered bicyclic aromatic carbocycle, 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is optionally substituted C 1-6 In some embodiments, R 7 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. 7 is optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. 7 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 7 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0263] In some embodiments, R 7 In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0264] In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0265] In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R7 yes In some embodiments, R 7 yes

[0266] In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0267] In some embodiments, R 7 Group and R 7 The ' group optionally forms a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring together with its intervening carbon atom. In some embodiments, R attached to the same carbon atom 7 Group and R 7 The ' group is optionally taken together with its intervening carbon atom to form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0268] In some embodiments, R 7 Select from those shown in Table 1 below.

[0269] As defined above and described herein, each R 7 ' are independently hydrogen or C 1-3 aliphatic.

[0270] In some embodiments, R 7’ In some embodiments, R 7’ In some embodiments, R 7’ In some embodiments, R 7’ In some embodiments, R 7’ It is isopropyl.

[0271] In some embodiments, R7' is selected from those shown in Table 1 below.

[0272] As defined above and described herein, each R8 are independently hydrogen or C 1-4 Aliphatic, or: R 8 Group and its adjacent R 7 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0273] In some embodiments, R 8 In some embodiments, R 8 It is C 1-4 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 It is tert-butyl.

[0274] In some embodiments, R 8 Group and its adjacent R 7 The group, together with its intervening atoms, forms a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0275] In some embodiments, R 8 Group and its adjacent R 7 The group together with its intervening atoms forms In some embodiments, R 8 Group and its adjacent R 7 The group together with its intervening atoms forms

[0276] In some embodiments, R 8 Select from those shown in Table 1 below.

[0277] As defined above and described herein, R 9 It is hydrogen, C 1-3 Aliphatic or -C(O)C 1-3 aliphatic.

[0278] In some embodiments, R 9 In some embodiments, R 9 It is C 1-3 In some embodiments, R 9 Yes-C(O)C 1-3 aliphatic.

[0279] In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 It is cyclopropyl.

[0280] In some embodiments, R 9 is -C(O)Me. In some embodiments, R 9 is -C(O)Et. In some embodiments, R 9 is -C(O)CH2CH2CH3. In some embodiments, R 9 is -C(O)CH(CH3)2. In some embodiments, R 9 It is -C(O)cyclopropyl.

[0281] In some embodiments, R 9 Select from those shown in Table 1 below.

[0282] In some embodiments, R is as described in the present disclosure. 7 In some embodiments, R a2 is R as described in this disclosure 7 In some embodiments, R a3 is R as described in this disclosure 7 In some embodiments, R is as described in the present disclosure. 7’ In some embodiments, R a2 is R as described in this disclosure 7’ In some embodiments, R a3 is R as described in this disclosure 7’ In some embodiments, R is as described in the present disclosure. 8 In some embodiments, R a2 is R as described in this disclosure 8 In some embodiments, R a3 is R as described in this disclosure 8 In some embodiments, R is as described in the present disclosure. 8’ In some embodiments, R a2 is R as described in this disclosure 8’ In some embodiments, R a3 is R as described in this disclosure 8’ In some embodiments, R is as described in the present disclosure.9 In some embodiments, R a2 is R as described in this disclosure 9 In some embodiments, R a3 is R as described in this disclosure 9 .

[0283] As defined above and described herein, L 3 It will A divalent linker moiety connected to TBT.

[0284] In some embodiments, L 3 It will A divalent linker moiety connected to TBT.

[0285] In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes

[0286] In some embodiments, L 3 Select from those shown in Table 1 below.

[0287] In some embodiments, L is L as described in the present disclosure. 3 .

[0288] As defined above and described herein, o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0289] In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. In some embodiments, o is 6. In some embodiments, o is 7. In some embodiments, o is 8. In some embodiments, o is 9. In some embodiments, o is 10.

[0290] In some embodiments, o is selected from those shown in Table 1 below.

[0291] In certain embodiments, the present invention provides compounds of formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-a or a pharmaceutically acceptable salt thereof: Among them L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and described in the embodiments herein, both alone and in combination.

[0292] In certain embodiments, the present invention provides a compound of formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-b or a pharmaceutically acceptable salt thereof: Among them L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and described in the embodiments herein, both alone and in combination.

[0293] In certain embodiments, the present invention provides compounds of formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-c or a pharmaceutically acceptable salt thereof: Among them L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and described in the embodiments herein, both alone and in combination.

[0294] In certain embodiments, the present invention provides compounds of formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-d or a pharmaceutically acceptable salt thereof: Among them L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and described in the embodiments herein, both alone and in combination.

[0295] In certain embodiments, the present invention provides compounds of formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-e or a pharmaceutically acceptable salt thereof: Among them L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and described in the embodiments herein, both alone and in combination.

[0296] In certain embodiments, the present invention provides compounds of formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-f or a pharmaceutically acceptable salt thereof: Among them L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and described in the embodiments herein, both alone and in combination.

[0297] In some embodiments, R a1 is R as described in the present disclosure. In some embodiments, Ra1 is optionally substituted C 1-4 aliphatic.

[0298] In some embodiments, L a1 is L as described in this disclosure a In some embodiments, L a1 It is a covalent bond.

[0299] In some embodiments, L a2 is L as described in this disclosure a In some embodiments, L a2 It is a covalent bond.

[0300] In some embodiments, L a is a covalent bond. In some embodiments, L a is optionally substituted and selected from C1-C 10 aliphatic or C1-C ... 10 A heteroaliphatic divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-. In some embodiments, L a is an optionally substituted divalent group selected from a C1-C5 aliphatic or a C1-C5 heteroaliphatic having 1 to 5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-. In some embodiments, L ais an optionally substituted divalent C1-C5 aliphatic, wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-. In some embodiments, L a L is an optionally substituted divalent C1-C5 aliphatic. a is an optionally substituted divalent C1-C5 heteroaliphatic having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0301] In some embodiments, R a2 is R as described in the present disclosure. In some embodiments, R a2 is a side chain of a natural amino acid. a3 is R as described in the present disclosure. In some embodiments, R a3 is a side chain of a natural amino acid. 2a and R 3a One is hydrogen.

[0302] In some embodiments, each -Cy- is independently an optionally substituted divalent group selected from: C 3-20 Cycloaliphatic ring, C 6-20 aryl rings, 5- to 20-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is optionally substituted as in the present disclosure, for example, for R and Cy L The ring described, but is divalent.

[0303] In some embodiments, -Cy- is monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- comprises a saturated cyclic moiety. In some embodiments, -Cy- comprises a partially unsaturated cyclic moiety. In some embodiments, -Cy- comprises an aromatic cyclic moiety. In some embodiments, -Cy- comprises a combination of saturated, partially unsaturated, and / or aromatic cyclic moieties. In some embodiments, -Cy- is 3-membered. In some embodiments, -Cy- is 4-membered. In some embodiments, -Cy- is 5-membered. In some embodiments, -Cy- is 6-membered. In some embodiments, -Cy- is 7-membered. In some embodiments, -Cy- is 8-membered. In some embodiments, -Cy- is 9-membered. In some embodiments, -Cy- is 10-membered. In some embodiments, -Cy- is 11-membered. In some embodiments, -Cy- is 12-membered. In some embodiments, -Cy- is 13-membered. In some embodiments, -Cy- is 14-membered. In some embodiments, -Cy- is 15-membered. In some embodiments, -Cy- is 16-membered. In some embodiments, -Cy- is 17-membered. In some embodiments, -Cy- is 18-membered. In some embodiments, -Cy- is 19-membered. In some embodiments, -Cy- is 20-membered.

[0304] In some embodiments, -Cy- is an optionally substituted divalent C 3-20 In some embodiments, -Cy- is an optionally substituted divalent saturated C 3-20 In some embodiments, -Cy- is an optionally substituted divalent partially unsaturated C 3-20 Cycloaliphatic Ring. In some embodiments, -Cy-H is an optionally substituted cycloaliphatic as described in the disclosure, for example, a cycloaliphatic embodiment of R.

[0305] In some embodiments, -Cy- is optionally substituted C 6-20In some embodiments, -Cy- is an optionally substituted phenylene ring. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene ring. In some embodiments, -Cy- is an optionally substituted 1,3-phenylene ring. In some embodiments, -Cy- is an optionally substituted 1,4-phenylene ring. In some embodiments, -Cy- is an optionally substituted divalent naphthalene ring. In some embodiments, -Cy-H is an optionally substituted aryl ring as described in the present disclosure, for example, an aryl embodiment of R.

[0306] In some embodiments, -Cy- is an optionally substituted divalent 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy-H is an optionally substituted heteroaryl as described in the disclosure, for example, a heteroaryl embodiment of R. In some embodiments, -Cy- is

[0307] In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 3- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted saturated divalent heterocyclyl. In some embodiments, -Cy- is an optionally substituted partially unsaturated divalent heterocyclyl. In some embodiments, -Cy-H is an optionally substituted heterocyclyl as described in the present disclosure, for example, the heterocyclyl embodiments of R.

[0308] In some embodiments, each Xaa is independently an amino acid residue. In some embodiments, each Xaa is independently an amino acid residue of an amino acid of formula AI.

[0309] In some embodiments, t is 0. In some embodiments, t is 1 to 50. In some embodiments, t is z as described in the disclosure.

[0310] In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10. In some embodiments, z is 11. In some embodiments, z is 12. In some embodiments, z is 13. In some embodiments, z is 14. In some embodiments, z is 15. In some embodiments, z is 16. In some embodiments, z is 17. In some embodiments, z is 18. In some embodiments, z is 19. In some embodiments, z is 20. In some embodiments, z is greater than 20.

[0311] In some embodiments, R c is R' as described in the present disclosure. In some embodiments, R c is R as described in the present disclosure. In some embodiments, R c is -N(R')2, wherein each R' is independently as described in the present disclosure. In some embodiments, R c is -NH2. In some embodiments, R c is RC(O)-, wherein R is as described in the disclosure.

[0312] In some embodiments, a is 1. In some embodiments, a is 2 to 100. In some embodiments, a is 5. In some embodiments, a is 10. In some embodiments, a is 20. In some embodiments, a is 50.

[0313] In some embodiments, b is 1. In some embodiments, b is 2 to 100. In some embodiments, b is 5. In some embodiments, b is 10. In some embodiments, b is 20. In some embodiments, b is 50.

[0314] In some embodiments, a1 is 0. In some embodiments, a1 is 1.

[0315] In some embodiments, a2 is 0. In some embodiments, a2 is 1.

[0316] In some embodiments, L b is L as described in this disclosure a In some embodiments, L b Contains -Cy-. In some embodiments, L b Contains a double bond. In some embodiments, L b Contains -S-. In some embodiments, L b Contains -SS-. In some embodiments, L b Contains -C(O)-N(R')-.

[0317] In some embodiments, R' is -R, -C(O)R, -C(O)OR, or -S(O)2R, wherein R is as described in the disclosure. In some embodiments, R' is R, wherein R is as described in the disclosure. In some embodiments, R' is -C(O)R, wherein R is as described in the disclosure. In some embodiments, R' is -C(O)OR, wherein R is as described in the disclosure. In some embodiments, R' is -S(O)2R, wherein R is as described in the disclosure. In some embodiments, R' is hydrogen. In some embodiments, R' is not hydrogen. In some embodiments, R' is R, wherein R is optionally substituted C as described in the disclosure. 1-20 In some embodiments, R' is R, wherein R is optionally substituted as described in the present disclosure. 1-20 In some embodiments, R' is R, wherein R is optionally substituted as described in the present disclosure. 6-20 In some embodiments, R' is R, wherein R is optionally substituted as described in the present disclosure. 6-20 In some embodiments, R' is R, wherein R is optionally substituted as described in the present disclosure. 6-20 In some embodiments, R' is R, wherein R is an optionally substituted 5- to 20-membered heteroaryl as described in the present disclosure. In some embodiments, R' is R, wherein R is an optionally substituted 3- to 20-membered heterocyclyl as described in the present disclosure. In some embodiments, two or more R's are R and optionally and independently taken together form an optionally substituted ring as described in the present disclosure.

[0318] In some embodiments, each R is independently -H, or an optionally substituted group selected from: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form together a covalent bond, or: two or more R groups on the same atom optionally and independently taken together with that atom form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to that atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0319] In some embodiments, each R is independently -H, or an optionally substituted group selected from: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form together a covalent bond, or: Two or more R groups on the same atom are optionally and independently taken together with that atom to form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to that atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0320] In some embodiments, each R is independently -H, or an optionally substituted group selected from: C 1-20 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-20 Heteroaliphatic, C 6-20 Aryl, C 6-20 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-20 arylheteroaliphatic, 5- to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 20-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form together a covalent bond, or: Two or more R groups on the same atom are optionally and independently taken together with that atom to form an optionally substituted 3- to 20-membered monocyclic, bicyclic or polycyclic ring having, in addition to that atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3- to 20-membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0321] In some embodiments, each R is independently -H, or an optionally substituted group selected from: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 Arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0322] In some embodiments, each R is independently -H, or an optionally substituted group selected from: C 1-20 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-20 Heteroaliphatic, C 6-20 Aryl, C 6-20 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-20 Arylheteroaliphatic, 5- to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0323] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen. In some embodiments, R is an optionally substituted group selected from the group consisting of: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30Aryl, 5- to 30-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 30-membered heterocyclic rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0324] In some embodiments, R is hydrogen or an optionally substituted group selected from: C 1-20 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8- to 10-membered bicyclic saturated, partially unsaturated or aryl ring, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0325] In some embodiments, R is optionally substituted C 1-30 In some embodiments, R is optionally substituted C 1-20 In some embodiments, R is optionally substituted C 1-15 In some embodiments, R is optionally substituted C 1-10 In some embodiments, R is optionally substituted C 1-6 In some embodiments, R is optionally substituted C 1-6 In some embodiments, R is an optionally substituted hexyl, pentyl, butyl, propyl, ethyl, or methyl group. In some embodiments, R is an optionally substituted hexyl group. In some embodiments, R is an optionally substituted pentyl group. In some embodiments, R is an optionally substituted butyl group. In some embodiments, R is an optionally substituted propyl group. In some embodiments, R is an optionally substituted ethyl group. In some embodiments, R is an optionally substituted methyl group. In some embodiments, R is a hexyl group. In some embodiments, R is a pentyl group. In some embodiments, R is a butyl group. In some embodiments, R is a propyl group. In some embodiments, R is an ethyl group. In some embodiments, R is a methyl group. In some embodiments, R is an isopropyl group. In some embodiments, R is an n-propyl group. In some embodiments, R is a tert-butyl group. In some embodiments, R is a sec-butyl group. In some embodiments, R is an n-butyl group. In some embodiments, R is -(CH2)2CN.

[0326] In some embodiments, R is optionally substituted C 3-30 In some embodiments, R is optionally substituted C 3-20In some embodiments, R is optionally substituted C 3-10 Cycloaliphatic. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0327] In some embodiments, R is an optionally substituted 3-30 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 5 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 6 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted cycloheptyl. In some embodiments, R is cycloheptyl. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0328] In some embodiments, when R is or comprises a ring structure such as a cycloaliphatic, cycloheteroaliphatic, aryl, heteroaryl, etc., the ring structure can be monocyclic, bicyclic, or polycyclic. In some embodiments, R is or comprises a monocyclic structure. In some embodiments, R is or comprises a bicyclic structure. In some embodiments, R is or comprises a polycyclic structure.

[0329] In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms. 1-20 In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, or silicon (optionally including one or more oxidized forms of nitrogen, sulfur, phosphorus, or selenium). 1-20In some embodiments, R is optionally substituted C 1-30 Heteroaliphatic comprising 1 to 10 groups independently selected from: -N=, ≡N, -S-, -S(O)-, -S(O)2-, -O-, =O,

[0330] In some embodiments, R is optionally substituted C 6-30 In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is a phenyl group. In some embodiments, R is a substituted phenyl group.

[0331] In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic saturated ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic partially unsaturated ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic aryl ring. In some embodiments, R is an optionally substituted naphthyl.

[0332] In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0333] In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, R is a substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.

[0334] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0335] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted pyrrolyl, furanyl, or thienyl.

[0336] In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered heteroaryl ring having one nitrogen atom and additional heteroatoms selected from sulfur or oxygen. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0337] In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In other embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having four nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having three nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having two nitrogen atoms. In certain embodiments, R is an optionally substituted 6-membered heteroaryl ring having one nitrogen atom.

[0338] In certain embodiments, R is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0339] In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0340] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-7 membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-6 membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-membered heterocyclic ring having one heteroatom independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 4-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0341] In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0342] In certain embodiments, R is an optionally substituted 5-6 membered partially unsaturated monocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted tetrahydropyridinyl, dihydrothiazolyl, dihydro Azolyl or Oxazoline.

[0343] In some embodiments, R is an optionally substituted 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted indolinyl. In some embodiments, R is an optionally substituted isoindolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroquinolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, R is an optionally substituted azabicyclo[3.2.1]octyl.

[0344] In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0345] In some embodiments, R is optionally substituted C 6-30 In some embodiments, R is an optionally substituted C 6-20 In some embodiments, R is an optionally substituted C 6-10In some embodiments, the aryl moiety in the aryl aliphatic group has 6, 10, or 14 aryl carbon atoms. In some embodiments, the aryl moiety in the aryl aliphatic group has 6 aryl carbon atoms. In some embodiments, the aryl moiety in the aryl aliphatic group has 10 aryl carbon atoms. In some embodiments, the aryl moiety in the aryl aliphatic group has 14 aryl carbon atoms. In some embodiments, the aryl moiety is an optionally substituted phenyl group.

[0346] In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-30 In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-20 In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-20 In some embodiments, R is an optionally substituted C having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-10 In some embodiments, R is an optionally substituted C having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-10 Arylheteroaliphatic.

[0347] In some embodiments, two R groups optionally and independently form a covalent bond together. In some embodiments, -C=O is formed. In some embodiments, -C=C- is formed. In some embodiments, -C≡C- is formed.

[0348] In some embodiments, two or more R groups on the same atom optionally and independently form with the atom an optionally substituted 3 to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form with the atom an optionally substituted 3 to 20-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form with the atom an optionally substituted 3-10-membered monocyclic, bicyclic, or polycyclic ring having 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-6 membered monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted 3-5 membered monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atom.

[0349] In some embodiments, two or more R groups on two or more atoms optionally and independently form with their intervening atoms an optionally substituted 3 to 30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form with their intervening atoms an optionally substituted 3 to 20 membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form with their intervening atoms an optionally substituted 3-10 membered monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups on two or more atoms optionally and independently form with their intervening atoms an optionally substituted 3-10 membered monocyclic, bicyclic, or polycyclic ring having from 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form with their intervening atoms an optionally substituted 3-6 membered monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form with their intervening atoms an optionally substituted 3-5 membered monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the intervening atoms.

[0350] In some embodiments, the heteroatoms in the R group or in the structure formed by two or more R groups are selected from oxygen, nitrogen and sulfur. In some embodiments, the ring formed is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 members. In some embodiments, the ring formed is saturated. In some embodiments, the ring formed is partially saturated. In some embodiments, the ring formed is aromatic. In some embodiments, the ring formed comprises a saturated, partially saturated or aromatic ring portion. In some embodiments, the ring formed comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 aromatic ring atoms. In some embodiments, the ring formed comprises no more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 aromatic ring atoms. In some embodiments, the aromatic ring atoms are selected from carbon, nitrogen, oxygen, and sulfur.

[0351] In some embodiments, the ring formed by two or more R groups (or two or more groups selected from R and variables that can be R) together is C 3-30 Cycloaliphatic, C 6-30 aryl, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, a ring as described for R, but divalent or multivalent.

[0352] Exemplary compounds of the present invention are listed in Table 1 below. Table 1. Exemplary compounds

[0353] In some embodiments, the present invention provides a compound listed in Table 1 above, or a pharmaceutically acceptable salt thereof. 4. General Methods for Providing Compounds of the Invention

[0354] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds and by the methods described in detail in the Examples herein.

[0355] In the following schemes, when a specific protecting group ("PG"), leaving group ("LG"), or transformation condition is described, one of ordinary skill in the art will understand that other protecting groups, leaving groups, and transformation conditions are also suitable and contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5 th Edition, John Wiley & Sons, 2001; Comprehensive Organic Transformations, RC Larock, 2 nd Edition, John Wiley & Sons, 1999; and Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3 rd edition, John Wiley & Sons, 1999, the entire contents of each of which are hereby incorporated by reference.

[0356] As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogen (e.g., fluoride, chloride, bromide, iodide), sulfonate (e.g., methanesulfonate, toluenesulfonate, benzenesulfonate, brosylate, nosylate, triflate), diazo, and the like.

[0357] The phrase "oxy protecting group" as used herein includes, for example, carbonyl protecting groups, hydroxy protecting groups, etc. Hydroxyl protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rdThe invention relates to a group comprising a hydroxyl protecting group comprising a hydroxyl protecting group. The group comprising a hydroxyl protecting group comprises a hydroxyl protecting group comprising ... Some specific examples include formates, benzoyl formates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (pivaloyl), crotonates, 4-methoxycrotonates, benzoates, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Some examples of such silyl ethers include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, tert-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, β-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Some examples of aryl alkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-pyridylmethyl.

[0358] Amino protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd ed., John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Some examples of such groups include tert-butyloxycarbonyl (BOC), ethoxycarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0359] It will be understood by those skilled in the art that compounds of Formula I, II or III may contain one or more stereocenters and may exist as racemic mixtures or diastereomeric mixtures. It will also be understood by those skilled in the art that many methods are known in the art for separating isomers to obtain stereoenriched or stereopure isomers of these compounds, including but not limited to HPLC, chiral HPLC, fractional crystallization of diastereomeric salts, kinetic enzymatic resolution (e.g., by lipases or esterases of fungal, bacterial or animal origin), and the use of enantiomeric enrichment agents to form covalent diastereomeric derivatives.

[0360] Those skilled in the art will appreciate that the various functional groups present in the compounds of the present invention (e.g., aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles) can be interconverted by techniques well known in the art, including but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Examples.

[0361] In some embodiments, the present disclosure provides compounds that can be used to prepare ARMs. In some embodiments, the present disclosure provides compounds that can be used to construct ARM molecules through cycloaddition reactions (e.g., click chemistry or variants thereof).

[0362] In some embodiments, the present disclosure provides a compound having the structure of Formula IV or a salt thereof: in: ABT is the antibody binding portion; L is the connector part; R d Yes-L a -R', where R d Contains -C≡C- or -N3; Each L a are independently covalent bonds, or optionally substituted selected from C1-C 20 aliphatic or C1-C ... 20a heteroaliphatic divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently an optionally substituted divalent group selected from the group consisting of: C 3-20 Cycloaliphatic ring, C 6-20 aryl rings, 5- to 20-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or an optionally substituted group selected from the group consisting of: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form together a covalent bond, or: two or more R groups on the same atom optionally and independently taken together with that atom form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to that atom, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0363] In some embodiments, the present disclosure provides a compound of Formula IV-a or a salt thereof: wherein each variable is independently as described in this disclosure.

[0364] In some embodiments, the present disclosure provides a compound of Formula IV-b or a salt thereof: R c -(Xaa) z -LR d IV-b, wherein each variable is independently as described in this disclosure.

[0365] In some embodiments, the present disclosure provides a compound of Formula IV-c or a salt thereof: wherein each variable is independently as described in this disclosure.

[0366] In some embodiments, the present disclosure provides a compound of Formula IV-d or a salt thereof: wherein each variable is independently as described in this disclosure.

[0367] In some embodiments, the present disclosure provides a compound of Formula V or a salt thereof: wherein each variable is independently as described in this disclosure.

[0368] In some embodiments, the present disclosure provides a method for preparing a compound comprising the steps of: providing a first compound of Formula IV, IV-a, IV-b, IV-c, or IV-d, or a salt thereof, wherein the compound comprises a first reactive moiety; Providing a second compound of Formula V or a salt thereof comprising a second reactive moiety; and reacting the first compound with the second compound, wherein the first reactive moiety reacts with the second reactive moiety via a cycloaddition reaction.

[0369] According to the present disclosure, many cycloaddition reactions can be utilized. In some embodiments, the cycloaddition reaction is a [4+2] reaction. In some embodiments, the cycloaddition reaction is a [3+2] reaction. In some embodiments, the [3+2] reaction is a click chemistry reaction. In some embodiments, the first reactive moiety is -C≡C-, and the second reactive moiety is -N3. In some embodiments, the first reactive moiety is -N3, and the second reactive moiety is -C≡C-. 5. Use, preparation and application Pharmaceutically acceptable compositions

[0370] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, excipient or vehicle. The amount of the compound in the composition of the present invention is such that endogenous antibodies are effectively selectively redirected to diseased cells, such as cancer cells, thereby inducing antibody-directed cell-mediated immunity, such as cytotoxicity. In certain embodiments, the amount of the compound in the composition of the present invention is such that endogenous antibodies are effectively selectively redirected to cancer cells, thereby inducing antibody-directed cell-mediated cytotoxicity in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0371] As used herein, the term "patient" refers to an animal, preferably a mammal, most preferably a human.

[0372] The term "pharmaceutically acceptable carrier, excipient or vehicle" refers to a non-toxic carrier, excipient or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, excipients or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0373] "Pharmaceutically acceptable derivative" refers to any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof.

[0374] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention can be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media.

[0375] For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids (e.g., oleic acid) and their glyceride derivatives can be used to prepare injections, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants commonly used in the preparation of pharmaceutically acceptable solids, liquids, or other dosage forms, such as Tween, Span, and other emulsifiers or bioavailability enhancers can also be used for formulation purposes.

[0376] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is desired for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0377] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0378] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0379] Topical application to the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0380] For topical application, the pharmaceutically acceptable compositions provided can be formulated with a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated with a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0381] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative (e.g., benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0382] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0383] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0384] The amount of the compound of the invention that can be combined with the carrier materials to produce a single dosage form of the composition will vary depending on the host being treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0385] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition. Uses of compounds and pharmaceutically acceptable compositions

[0386] The compounds and compositions described herein are generally useful for selectively redirecting endogenous antibodies to diseased cells, such as cancer cells, thereby inducing an antibody-directed cell-mediated immune response, such as cytotoxicity.

[0387] In some embodiments, present disclosure provides a method for raising antibodies (e.g., endogenous antibodies) to a target, comprising contacting the target with a provided agent, compound, or composition. In some embodiments, the antibodies raised comprise one or more endogenous antibodies. In some embodiments, the antibodies raised are specific for one or more antigens. In some embodiments, the antibodies raised are specific for one or more peptide antigens or proteins. In some embodiments, the antibodies raised are heterogeneous because they are not antibodies to the same antigen or protein.

[0388] In some embodiments, the present disclosure provides methods for recruiting immune cells to a target, comprising contacting the target with a provided agent, compound, or composition.

[0389] In some embodiments, present disclosure provides a method for triggering, producing, promoting and / or enhancing one or more immune system activities for a target, comprising contacting the target with a provided agent, compound or composition. In some embodiments, immune system activity is or comprises ADCC. In some embodiments, immune system activity is or comprises ADCP. In some embodiments, immune system activity is or comprises both ADCC and ADCP. In some embodiments, immune system activity is or comprises complement dependent cytotoxicity (CDC). In some embodiments, immune system activity is or comprises ADCVI.

[0390] In some embodiments, the target is a cancer cell. In some embodiments, the target is a cancer cell in a subject. In some embodiments, provided methods include administering a provided agent, compound, or composition to a subject.

[0391] In some embodiments, when in contact with their target, provided agents and compounds form a complex with an antibody and an Fc receptor on a target cell. In some embodiments, the disclosure provides a complex comprising: A medicament comprising: Antibody binding portion, a target binding moiety, and an optional linker moiety; Fc region; and Fc receptors, The antibody binding portion is a universal antibody binding portion.

[0392] In some embodiments, the present disclosure provides a complex comprising two or more complexes each independently comprising: A medicament comprising: Antibody binding portion, a target binding moiety, and an optional linker moiety; Fc region; and Fc receptors, The Fc regions in the complex are antibodies and / or fragments thereof directed against different antigens or proteins.

[0393] In some embodiments, the Fc regions in the complex are from antibodies and / or fragments thereof directed against different proteins. In some embodiments, one or more Fc regions are from endogenous antibodies and / or fragments thereof.

[0394] The term "treatment" as used herein refers to the reversal of a disease or disorder as described herein or one or more of its symptoms, alleviation, the delay of its occurrence or the suppression of its progress. In some embodiments, treatment can be administered after one or more symptoms occur. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to susceptible individuals before symptoms occur (for example, according to symptom history and / or according to heredity or other susceptibility factors). Treatment can also be continued after symptoms subside, for example, to prevent or delay its recurrence.

[0395] In some embodiments, the present invention provides methods for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is cancer.

[0396] The term "neoplasia" or "cancer" as used throughout this specification refers to the pathological process that leads to the formation and growth of a cancerous or malignant neoplasm, i.e., an abnormal tissue that grows by cell proliferation, usually more rapidly than normal, and continues to grow after the stimulus that initiated new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination compared to normal tissue, most invade surrounding tissues, metastasize to multiple sites, and may recur after attempted resection and cause the patient's death unless appropriate treatment is administered. The term neoplasia as used herein is used to describe all cancerous disease states and encompasses or includes pathological processes associated with malignant hematogenous, ascites, and solid tumors. Some representative cancers include, for example, prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine corpus cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer and lymphoma, etc., which can be treated by one or more compounds according to the present invention. Among other things, the provided technology (eg, compounds, compositions, methods, etc.) is particularly useful for preventing and / or treating cancer.

[0397] Furthermore, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for the preparation of a medicament for the treatment of a proliferative disease. Combination treatment

[0398] Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition can be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0399] In certain embodiments, provided combinations or compositions thereof are administered in combination with an additional therapeutic agent.

[0400] Examples of agents that may also be combined with the present invention include, but are not limited to, those used in the treatment of Alzheimer's Disease, such as and For the treatment of HIV, such as ritonavir; for the treatment of Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; for the treatment of multiple sclerosis (MS), such as beta interferon (e.g. and ), and mitoxantrone; used in the treatment of asthma, such as albuterol and Agents used to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and Haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, and sirolimus. neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and anti-Parkinson's disease agents; agents for the treatment of cardiovascular diseases such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for the treatment of liver diseases such as corticosteroids, cholestyramine, interferon and antiviral agents; agents for the treatment of blood diseases such as corticosteroids, anti-leukemia agents and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., metabolic breakdown inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and agents for the treatment of immunodeficiency diseases such as gamma globulin.

[0401] In certain embodiments, the combination therapies of the invention, or pharmaceutically acceptable compositions thereof, are administered in combination with a monoclonal antibody or siRNA therapeutic.

[0402] These additional agents can be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, these agents can be part of a single dosage form, mixed with the compounds of the invention in a single composition. If administered as part of a multiple-dose regimen, the two active agents can be administered simultaneously, sequentially, or within a period of time of each other (usually within five hours of each other).

[0403] The terms "combination," "combined," and related terms used herein refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combination of the present invention can be administered simultaneously or sequentially with the additional therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0404] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein is between about 50% and 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0405] In one embodiment, the invention provides compositions comprising Formula I, II or III compound and one or more other therapeutic agents.The therapeutic agent can be applied together with Formula I, II or III compound, or can be applied before or after Formula I, II or III compound is applied.Suitable therapeutic agent is described in further detail below.In certain embodiments, Formula I, II or III compound can be applied at most 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours before the therapeutic agent. In other embodiments, the compound of Formula I, II or III can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours after the therapeutic agent.

[0406] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents. Such additional therapeutic agents can be small molecules or recombinant biological agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac, dapoxetine, spironolactone, dapoxetine ... and celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat Sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine methotrexate Gold salts such as gold glucosinolate gold thiomalate and Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents such as etanercept infliximab Golimumab Certolizumab pegol and adalimumab "Anti-IL-1" agents, such as anakinra and rilonacept canakinumab Anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab "Anti-T cell" agents such as abatacept "Anti-IL-6" agents such as tocilizumab Diclofenac, cortisone, hyaluronic acid ( or ), monoclonal antibodies such as tanezumab, anticoagulants such as heparin ( or ) and warfarin Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine and alosetron lubiprostone Laxatives such as Milk of Magnesia, polyethylene glycol and Anticholinergics or antispasmodics such as dicyclomine Beta-2 agonists such as salbutamol ( HFA, HFA), levalbuterol Metaproterenol pirbuterolacetate terbutaline sulfate salmeterol xinafoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium Inhaled corticosteroids such as beclomethasone dipropionate ( and ), triamcinolone acetonide mometasone budesonide and flunisolide Cromolyn sodium Methylxanthines such as theophylline and aminophylline, IgE antibodies such as omalizumab Nucleoside reverse transcriptase inhibitors such as zidovudine Abacavir Abacavir / lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors such as delavirdine Efavirenz Nevairapine and etravirine Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as amprenavir Atazanavir Darunavir fosamprenavir indinavir Lopinavir and ritonavir nelfinavir Ritonavir Saquinavir ( or ) and tipranavir Entry inhibitors such as enfuvirtide and maraviroc Integrase inhibitors such as raltegravir doxorubicin vincristine Bortezomib and dexamethasone With lenalidomide or any combination thereof.

[0407] In another embodiment, the present invention provides a method of treating gout comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and febuxostat

[0408] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as gold glucosinolate gold thiomalate and Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents such as etanercept Infliximab Golimumab Certolizumab and adalimumab "Anti-IL-1" agents such as anakinra and Linacept Antibodies such as rituximab "Anti-T cell" agents such as abatacept and "anti-IL-6" agents such as tocilizumab

[0409] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, diclofenac, cortisone, hyaluronic acid ( or ) and monoclonal antibodies such as tariizumab.

[0410] In some embodiments, the present invention provides a method of treating lupus comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarials such as hydroxychloroquine and chloroquine Cyclophosphamide Methotrexate Azathioprine and anticoagulants such as heparin ( or ) and warfarin

[0411] In some embodiments, the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from the group consisting of mesalamine Sulfasalazine Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine and alosetron Lubiprostone Laxatives such as milk of magnesia, polyethylene glycol and and anticholinergics or antispasmodics such as dicyclomine Anti-TNF therapy, steroids, and antibiotics such as nanomicin (Flagyl) or ciprofloxacin.

[0412] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from: Beta-2 agonists such as salbutamol ( HFA, HFA), levorotatory salbutamol Ocenet Piributerol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone budesonide Flunisolide and Sodium cromoglycate Methylxanthines such as theophylline and aminophylline, and IgE antibodies such as omalizumab

[0413] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from the group consisting of beta-2 agonists such as albuterol ( HFA, HFA), levorotatory salbutamol Ocenet Piributerol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium bromide Methylxanthines such as theophylline and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone budesonide Flunisolide and

[0414] In some embodiments, the present invention provides a method of treating HIV comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from the group consisting of nucleoside reverse transcriptase inhibitors such as zidovudine Abacavir Abacavir / Lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors such as delavirdine Efavirenz Nevirapine and etravirine Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir ( or ) and tipranavir Entry inhibitors such as enfuvirtide and Maravero Integrase inhibitors such as raltegravir and combinations thereof.

[0415] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from the group consisting of: rituximab Cyclophosphamide Doxorubicin vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0416] In another embodiment, the present invention provides a method of treating solid tumors comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide Doxorubicin vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0417] In another embodiment, the present invention provides a method for treating a hematologic malignancy comprising administering to a patient in need thereof a compound of Formula I, II, or III and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematologic malignancy is DLBCL (Ramirez et al "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online July 17 and incorporated herein by reference in its entirety).

[0418] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide Doxorubicin vincristine Prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0419] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from: bortezomib and dexamethasone Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors and lenalidomide combination.

[0420] In another embodiment, the present invention provides a method for treating Waldenstrom's macroglobulinemia ( macroglobulinemia) comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from: chlorambucil Cyclophosphamide fludarabine cladribine Rituximab Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0421] In some embodiments, the present invention provides a method of treating Alzheimer's disease comprising administering to a patient in need thereof a compound of Formula I, II, or III and one or more additional therapeutic agents selected from: donepezil rivastigmine Galantamine Tacrine and memantine

[0422] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, comprising administering to a patient in need thereof a compound of Formula I, II or III and one or more additional therapeutic agents selected from the group consisting of a steroid, cyclosporine, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0423] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of Formula I, II or III and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura,ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome), idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disease, transplant organ or tissue rejection, acquired immunodeficiency syndrome (AIDS). Immunodeficiency Syndrome, AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergic reactions (e.g.,Allergies to plant pollens, latex, drugs, foods, insect toxins, animal hair, animal dander, dust mites, or cockroach calyxes), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa suppurativa), immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tetanus, Pelvic inflammation, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma marginal zone B cell lymphoma), nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases, including but not limited to rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, thromboembolic disease (e.g.,Myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitus), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's syndrome, tissue graft rejection, hyperacute rejection of a transplanted organ, asthma, allergic rhinitis, chronic obstructive pulmonary disease disease, COPD), autoimmune polyglandular disease (also called autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes mellitus, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldner's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0424] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, II or III and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative diseases, angiogenic diseases, viral diseases, autoimmune diseases, inflammatory diseases, hormone-related diseases, diseases associated with organ transplantation, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune disorders involving T cell activation, cardiovascular disease and CNS disease.

[0425] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of Formula I, II or III and a PI3K inhibitor, wherein the disease is selected from the group consisting of: a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid; a sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer or colorectal adenoma or tumor of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial cells; character), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also known as Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia, diseases including Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced by bacterial infection, acute lung injury (acute lung injury), injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, and exacerbation of airway hyperresponsiveness caused by other drug therapy (especially other inhaled drug therapy), bronchitis of any type or origin, including but not limited to acute, arachidonic, catarrhal, croupus, chronic or tuberculous bronchitis, pneumoconiosis of any type or origin (an inflammatory, usually occupational lung disease, often with chronic or acute airway obstruction, caused by repeated inhalation of dust), including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosi, tabacosis and byssinosis, Loffler syndrome,Eosinophilia, pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas and eosinophil-related diseases affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratolysis sicca Conjunctivitis and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases in which an autoimmune reaction is involved or has an autoimmune component or etiology, including autoimmune blood diseases (such as hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, sprue), autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), endocrine eye diseases, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0426] The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route of administration that is effective in treating or alleviating the severity of cancer or a proliferative disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, and the like. For ease of administration and uniformity of dosage, the compounds of the present invention are preferably formulated in dosage unit form. As used herein, the expression "dosage unit form" refers to physically discrete units of a drug suitable for the patient to be treated. However, it should be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0427] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, once or more times a day to achieve the desired therapeutic effect.

[0428] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may also include inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, oral compositions may also include, for example, the following adjuvants: wetting agents, emulsifiers, and suspending agents, sweeteners, flavorings, and aromatics.

[0429] Injectable preparations can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable carriers and solvents that can be used are water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are typically used as solvents or suspending media. For this reason, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injections.

[0430] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0431] In order to prolong the effect of the compounds of the present invention, it is generally desirable to slow down the absorption of the compound from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oil carrier. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (e.g., polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Some examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations can also be prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0432] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0433] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets, and pills, the dosage form may also contain a buffer.

[0434] The solid composition of similar type can be used as the filler in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol etc. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared to have coatings or shells, such as other coatings known in the field of enteric coating and pharmaceutical formulations. It can optionally comprise an emulsifier and can also have a composition that only or preferentially releases the active ingredient in a delayed manner in some part of the intestinal tract. Some examples of operable embedding compositions include polymeric substances and wax. Using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol etc., the solid composition of similar type can also be used as the filler in soft and hard filled gelatin capsules.

[0435] Active compound can also be a microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared to have coatings or shells, such as enteric coatings, controlled release coatings and other coatings known in the field of pharmaceutical formulations. In such solid dosage forms, active compound can be mixed with at least one inert diluent (such as sucrose, lactose or starch). In conventional practice, such dosage forms can also include other substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. With regard to capsules, tablets and pills, dosage form can also include a buffer. It can optionally include an emulsifier, and can also have a composition that only or preferentially releases the active ingredient in a delayed manner in some parts of the intestinal tract. Some examples of usable embedding compositions include polymeric substances and waxes.

[0436] The dosage form for the surface or transdermal application of the compounds of this invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer (can be on demand) under aseptic conditions. Ophthalmic preparations, ear drops and eye drops are also considered to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing the controlled delivery of the compound to health. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to improve the flux of the compound through the skin. Rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0437] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0438] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids, or extracts thereof.

[0439] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0440] In particular, the compounds and / or compositions of the present disclosure can be used in combination therapy, that is, the compounds and / or compositions of the present disclosure can be administered simultaneously with, before, or after one or more other therapeutic agents or medical procedures, especially for the treatment of various cancers. In some embodiments, the compounds of the present invention can also be advantageously used in combination with other anti-proliferative compounds. The specific combination of treatments (therapeutic agents or procedures) employed in a combination regimen will take into account the compatibility of the desired other therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It should also be understood that the treatment employed can achieve the desired effect for the same disease (e.g., a provided compound can be administered simultaneously with another anti-cancer agent), or it can achieve a different effect (e.g., to control any adverse effects). In some embodiments, the therapeutic agent is a chemotherapeutic agent or anti-proliferative compound. Exemplary chemotherapeutic agents include, but are not limited to, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone therapy drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anti-cancer agents. In addition, the provided technology can be used together with leukopenia (neutrophil) drugs, thrombocytopenia drugs, antiemetics and cancer analgesics as adjuvants for cancer treatment for the recovery of the patient's QOL, or prepared into a mixture with them. In some embodiments, the therapeutic agent is an antibody. In some embodiments, the therapeutic agent is an immunomodulator. In some embodiments, the immunomodulator targets cell surface signaling molecules on immune cells. In some embodiments, the immunomodulator targets cell surface signaling molecules on immune cells, wherein the agent is an antagonist that blocks the co-inhibitory pathway. In some embodiments, the immunomodulator is a checkpoint blocker. In some embodiments, the immunomodulator is an antibody targeting a cell surface signaling protein expressed by an immune cell. In some embodiments, the immunomodulator is an antibody targeting a protein selected from PD-1, PD-L1, CTLA4, TIGIT, BTLA, TIM-3, LAG3, B7-H3 and B7-H4. In some embodiments, the immunomodulator is a PD-1 antibody (e.g., nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL328OA, etc.). In some embodiments, the immunomodulator is a PD-L1 antibody. In some embodiments, the immunomodulator is a CTLA4 antibody (e.g., ipilimumab). In some embodiments, the immunomodulator is a TIGIT antibody. In some embodiments, the immunomodulator is a BTLA antibody. In some embodiments, the immunomodulator is a Tim-3 antibody. In some embodiments, the immunomodulator is a LAG3 antibody.In some embodiments, the immunomodulator is a B7-H3 antibody. In some embodiments, the immunomodulator is a B7-H4 antibody. In some embodiments, the immunomodulator targets cell surface signaling molecules on immune cells, wherein the agent is an agonist that participates in a costimulatory pathway. In some embodiments, such an immunomodulator is or comprises an antibody targeting a costimulatory receptor. In some embodiments, the antibody activates T cell costimulatory receptors. In some embodiments, the antibody targets members of the tumor necrosis factor (TNF) receptor superfamily. In some embodiments, the antibody targets proteins selected from CD137 (4-1BB), CD357 (GITR, TNFRS18, AITR), CD134 (OX40), and CD 40 (TNFRSF5). In some embodiments, the antibody is an anti-CD137 antibody (e.g., urelumab). In some embodiments, the antibody is an anti-CD357 antibody. In some embodiments, the antibody is an anti-CD40 antibody. In some embodiments, the antibody is an anti-CD134 antibody. Additional exemplary T cell co-stimulatory and co-inhibitory receptors are described in: Chen L, Flies DB., Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013, 13(4), 227-42, and Yao S, et al., Advances intargeting cell surface signaling molecules for immune modulation. Nat. Rev. Drug Discov. 2013, 12(2), 136-40. In some embodiments, the therapeutic agent is an antibody that activates such a stimulatory receptor or blocks such an inhibitory receptor.

[0441] In some embodiments, one or more other therapeutic agents are or include tumor-specific immune cells. In some embodiments, one or more other therapeutic agents are or include tumor-specific T cells. In some embodiments, one or more other therapeutic agents are or include tumor-infiltrating lymphocytes (TIL). In some embodiments, one or more other therapeutic agents are or include T cells that ectopically express known anti-tumor T cell receptors (T cell receptor, TCR). In some embodiments, one or more other therapeutic agents are or include chimeric antigen receptor (CAR) T cells. In some embodiments, provided compositions include immune enhancing substances. Exemplary immune enhancing substances that can be used in combination with provided compounds, compositions and / or methods include but are not limited to a variety of cytokines and tumor antigens. Cytokines that stimulate immune responses include, for example, GM-CSF, M-CSF, G-CSF, interferon-α, interferon-β, interferon-γ, IL-1, IL-2, IL-3 and IL-12, etc. Antibodies that block inhibitory receptors and / or activate stimulatory receptors are widely known in the art and are described herein, such as, but not limited to, B7 ligand derivatives, anti-CD3 antibodies, anti-CD28 antibodies, and anti-CTLA-4 antibodies, which can also improve immune responses. In some embodiments, the therapeutic agent is a small molecule for immunomodulation. In some embodiments, the therapeutic agent is a small molecule that mediates anti-tumor immune activity. In some embodiments, the therapeutic agent is a small molecule that targets an enzyme directly involved in immunomodulation. In some embodiments, the therapeutic agent is an indoleamine 2,3-dioxygenase (IDO) inhibitor. In some embodiments, the therapeutic agent is an IDO1 inhibitor, such as F001287, indoximod, NLG-919, and INCB024360. In some embodiments, the therapeutic agent is a tryptophan-2,3-dioxygenase (TDO) inhibitor. In some embodiments, the therapeutic agent is an IDO / TDO dual inhibitor. In some embodiments, the therapeutic agent is an IDO selective inhibitor. In some embodiments, in some other embodiments, the therapeutic agent is a TDO selective inhibitor. In some embodiments, the compositions provided include an IDO inhibitor and a first construct. In some embodiments, the compositions provided include an IDO inhibitor, a first construct, and a second construct. It has been recognized that the immune response to the first construct and / or the second construct can be significantly enhanced by administering an IDO inhibitor.

[0442] In some embodiments, medical procedures that can be used in combination with the compounds, compositions, and methods of the present application include, but are not limited to, surgery, radiation therapy ( In some embodiments, the medical procedure is surgery. In some embodiments, the medical procedure is radiation therapy.

[0443] Antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target / decrease the activity of protein or lipid kinases and other antiangiogenic compounds; compounds that target, decrease or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; Biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, decrease, or inhibit Flt-3 activity; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide Kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and folinic acid. The term "aromatase inhibitor" as used herein relates to compounds that inhibit estrogen production, such as the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane, and in particular non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name Aromasin TM Formestane is sold under the trade name Lentaron TM Fadrozole is sold under the trade name Afema TM Anastrozole is sold under the trade name Arimidex TM Letrozole is sold under the trade name Femara TM or Femar TM Aminglutethimide is sold under the trade name Orimeten TM The combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0444] As used herein, the term "antiestrogen" refers to compounds that antagonize the effects of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex. TM Raloxifene hydrochloride is sold under the trade name Evista TM Fulvestrant is sold under the trade name Faslodex. TM Administration. Combinations of the invention comprising a chemotherapeutic agent that is an antiestrogen are particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors.

[0445] As used herein, the term "antiandrogen" refers to any substance capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (Casodex TM The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is available under the trade name Zoladex. TM Application.

[0446] As used herein, the term "topoisomerase I inhibitors" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan is commercially available, for example, under the trademark Camptosar®. TM Topotecan is marketed under the trade name Hycamptin TM Sale.

[0447] As used herein, the term "topoisomerase II inhibitors" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos TM Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin TM or Adriamycin TM Epirubicin is sold under the trade name Farmorubicin TM Idarubicin is sold under the trade name Zavedos TM Mitoxantrone is sold under the trade name Novantron.

[0448] The term "microtubule active agent" refers to microtubule stabilizers, microtubule destabilizing compounds and tubulin polymerization inhibitors, including but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilones and their derivatives. Paclitaxel is marketed under the trade name Taxol TM Docetaxel is sold under the trade name Taxotere TMVinblastine sulfate is sold under the trade name Vinblastin RP TM Vincristine sulfate is sold under the trade name Farmistin TM Sale.

[0449] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin TM Ifosfamide is sold under the trade name Holoxan TM Sale.

[0450] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0451] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexed, and folic acid antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda TM Gemcitabine is sold under the trade name Gemzar TM Sale.

[0452] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin (cis-platin, cisplatinum) and oxaliplatin. Carboplatin is commercially available, for example, under the trademark Carboplat TM Oxaliplatin can be administered, for example, in the form as it is marketed (e.g. under the trademark Eloxatin TM commercially available) form.

[0453] As used herein, the term "compounds that target / decrease the activity of a protein or lipid kinase, or a protein or lipid phosphatase; or other anti-angiogenic compounds" includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor-receptor (PDGFR), such as compounds that target, decrease or inhibit the activity of PDGFR, in particular compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit the activity of fibroblast growth factor-receptor (FGFR); c) compounds that target, decrease or inhibit the activity of insulin-like growth factor receptor I (IGF-1). I, IGF-IR) activity, such as compounds that target, reduce or inhibit IGF-IR activity, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-1 receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, decrease or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, decrease or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, decrease or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, decrease or inhibit the activity of the c-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, decrease or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from Parke Davis; or dasatinib (BMS-354825);j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and serine / threonine kinase Raf families, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives such as midostaurin; some examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isochinoline compounds. compound); FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, for example, compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrphostin, such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44(+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4, as homodimers or heterodimers) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family members (such as EGF receptor, ErbB2, ErbB3 and ErbB4) or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin TM ), Cetuximab (Erbitux TM), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease or inhibit the activity of the c-Met receptor, such as compounds that target, decrease or inhibit the activity of c-Met, especially compounds that inhibit the kinases of the c-Met receptor compounds that target, decrease or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-14 80, TG-101348, tofacitinib and ruxolitinib; o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-469150 2. BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and; and q) compounds that target, decrease or inhibit signaling through the hedgehog (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0454] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol 3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparcoxib, pectecoxib, PF-4691502, BYL-719, dactocoxib, XL-147, XL-765, and idecoxib.

[0455] The term "BTK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0456] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0457] Further examples of BTK-inhibiting compounds, and conditions that can be treated by such compounds in combination with the compounds of the present invention, can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0458] Further examples of SYK-inhibiting compounds, and conditions that can be treated by such compounds in combination with the compounds of the present invention, can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0459] Further examples of PI3K inhibitory compounds, and conditions that can be treated by such compounds in combination with the compounds of the present invention, can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0460] Further examples of JAK inhibitory compounds and conditions that can be treated by such compounds in combination with the compounds of the invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0461] Other anti-angiogenic compounds include compounds that have another mechanism of activity, for example, one that is not related to protein or lipid kinase inhibition, such as thalidomide. TM ) and TNP-470.

[0462] Examples of proteasome inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0463] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0464] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ-, or δ-tocopherol, or α-, γ-, or δ-tocotrienol.

[0465] The term cyclooxygenase inhibitors as used herein includes but is not limited to Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives such as celecoxib (Celebrex TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid (eg 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid), lumiracoxib.

[0466] As used herein, the term "bisphosphonates" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. TM Clodronate is sold under the trade name Bonefos TM Tiludronic acid is sold under the trade name Skelid TM Pamidronate is sold under the trade name Aredia TM Alendronate is sold under the trade name Fosamax TM Ibandronic acid is sold under the trade name Bondranat TM Risedronate is sold under the trade name Actonel TM Zoledronic acid is sold under the trade name Zometa TM The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus Everolimus (Certican TM ), CCI-779 and ABT578.

[0467] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparan sulfate. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0468] As used herein, the term "inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras or N-Ras" refers to a compound that targets, decreases or inhibits the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor," such as L-744832, DK8G557 or R115777 (Zarnestra TM As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits telomerase activity. Compounds that target, reduce, or inhibit telomerase activity are particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0469] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0470] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, reduce or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade TM ) and MLN341.

[0471] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) includes, but is not limited to, collagen peptidomimetics and non-peptide mimetic inhibitors, tetracycline derivatives such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0472] As used herein, the term "compounds for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranosine cytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0473] Compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0474] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins through the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: ABT is the antibody binding portion; L is a divalent linker moiety that connects ABT to TBT; and TBT is the target binding moiety.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula II: in: R 1 , R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from the following: C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8- to 10-membered bicyclic aromatic carbocycle, 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or: R 1 and R 1’ optionally together with its intervening carbon atom(s) form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3’ optionally together with its intervening carbon atom(s) form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R attached to the same carbon atom 5 Group and R 5’ The group optionally forms, together with its intervening carbon atom, a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or Two R's 5 The group optionally forms a C 1-10 A divalent straight or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally substituted with -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -C(O)-. 1 -replacement, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1’ , R 3’ and R 5’ are independently hydrogen or C 1-3 aliphatic; R 2 , R 4 and R 6 are independently hydrogen or C 1-4 Aliphatic, or: R 2 and R 1 optionally together with its intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 optionally together with its intervening atoms form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 6 Group and its adjacent R 5 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; L 1 Yes and a connected trivalent linker moiety; L 2 Is a covalent bond or C 1-10 A divalent straight or branched, saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally substituted by -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 -replacement, where each -Cy 1 - is independently a 5- to 6-membered heteroarylene group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; TBT is a target binding moiety; and m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula III: in: Each R 7 is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8- to 10-membered bicyclic aromatic carbocycle, 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or: R attached to the same carbon atom 7 Group and R 7’ The group optionally forms, together with its intervening carbon atom, a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; Each R 7’ are independently hydrogen or C 1-3 aliphatic; Each R 8 are independently hydrogen or C 1-4 Aliphatic, or: R 8 Group and its adjacent R 7 The group is optionally taken together with its intervening atoms to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 9 It is hydrogen, C 1-3 Aliphatic, or -C(O)C 1-3 aliphatic; L 3 Yes a divalent linker moiety connected to TBT; TBT is a target binding moiety; and o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The compound or salt thereof according to claim 1, wherein the compound has a structure of Formula Ia: in: Each Xaa is independently an amino acid residue; t is 0 to 50; z is 1 to 50; L is the joint part; TBT is the target binding moiety; Each R c Independently -L a -R'; a and b are each independently 1 to 200; Each L a are independently covalent bonds, or optionally substituted selected from C1-C 20 aliphatic or C1-C 20 a heteroaliphatic divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently an optionally substituted divalent group selected from the following: 3-20 Cycloaliphatic ring, C 6-20 aryl rings, 5- to 20-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 20-membered heterocyclyl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; Each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or an optionally substituted group selected from the group consisting of: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form a covalent bond together, or: two or more R groups on the same atom optionally and independently form with said atom an optionally substituted 3 to 30 membered monocyclic, bicyclic or polycyclic ring having in addition to said atom 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups on two or more atoms optionally and independently taken together with their intervening atoms form an optionally substituted 3 to 30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

5. The compound or salt thereof according to claim 1, wherein the compound has a structure of Formula Ib: in: Each Xaa is independently an amino acid residue; Each z is independently 1 to 50; Each L is independently a linker moiety; TBT is the target binding moiety, Each R c Independently -L a -R'; a1 and a2 are each independently 0 to 200, wherein at least one of a1 and a2 is not 0; b is 1 to 200; Each L a are independently covalent bonds, or optionally substituted selected from C1-C 20 aliphatic or C1-C 20 a heteroaliphatic divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, or -C(O)O-; Each -Cy- is independently an optionally substituted divalent group selected from the following: 3-20 Cycloaliphatic ring, C 6-20 aryl rings, 5- to 20-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 20-membered heterocyclyl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; Each R' is independently -R, -C(O)R, -CO2R, or -SO2R; Each R is independently -H, or an optionally substituted group selected from the group consisting of: C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or Two R groups optionally and independently form a covalent bond together, or: two or more R groups on the same atom optionally and independently form with said atom an optionally substituted 3 to 30 membered monocyclic, bicyclic or polycyclic ring having in addition to said atom 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups on two or more atoms optionally and independently taken together with their intervening atoms form an optionally substituted 3 to 30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a method for recruiting multiple antibodies to a target site using the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein the compound recruits multiple antibodies to the target site.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a method for selectively redirecting endogenous antibodies to diseased cells in a patient, thereby inducing antibody-directed cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) in the diseased cells, wherein the method comprises administering the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the patient.

9. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a method for selectively redirecting endogenous antibodies to diseased cells in a biological sample to induce antibody-directed cell-mediated cytotoxicity (ADCC) in the diseased cells, wherein the method comprises contacting the biological sample with the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

10. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating a disorder, disease or condition in a subject, wherein the method comprises administering to the subject the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Images